Androgen receptor modulators and uses thereof

ABSTRACT

Described herein are compounds that are androgen receptor modulators. Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods of using such androgen receptor modulators, alone and in combination with other compounds, for treating diseases or conditions that are mediated or dependent upon androgen receptors.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/656,031, filed on Mar. 12, 2015, which is a continuation of U.S.patent application Ser. No. 13/579,009, filed on Aug. 30, 2012, which isthe National Stage Entry of International Application No.PCT/US2011/025106, filed on Feb. 16, 2011, which claims the benefit ofpriority to U.S. Provisional Patent Application No. 61/305,082, filed onFeb. 16, 2010; 61/329,023, filed on Apr. 28, 2010; and 61/388,457, filedon Sep. 30, 2010, all of which are incorporated by reference in theirentireties.

FIELD OF THE INVENTION

Described herein are compounds, including pharmaceutically acceptablesalts, solvates, metabolites, prodrugs thereof, methods of making suchcompounds, pharmaceutical compositions comprising such compounds, andmethods of using such compounds to treat, prevent or diagnose diseasesor conditions that are androgen receptor dependent or androgen receptormediated.

BACKGROUND OF THE INVENTION

The androgen receptor (“AR”) is a ligand-activated transcriptionalregulatory protein that mediates induction of a variety of biologicaleffects through its interaction with with endogenous androgens.Endogenous androgens include steroids such as testosterone anddihydrotestosterone. Testosterone is converted to dihydrotestosterone bythe enzyme 5 alpha-reductase in many tissues.

The actions of androgens with androgen receptors have been implicated ina number of diseases or conditions, such as androgen dependent cancers,virilization in women, and acne, among others. Compounds that diminishthe effects of androgens with androgen receptors and/or lower the theconcentrations of androgen receptors find use in the treatment ofdiseases or conditions in which androgen receptors play a role.

SUMMARY OF THE INVENTION

In one aspect, presented herein are compounds of Formula (I), (Ia),(II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X)that diminish the effects of androgens with androgen receptors and/orlower the the concentrations of androgen receptors, and therefore, areuseful as agents for the treatment or prevention of diseases orconditions in which androgen receptors play a role, such as diseases orconditions in which androgen receptors participate, are involved in theetiology or pathology of the disease or condition, or contribute to atleast one symptom of the disease or condition.

In one aspect, compounds of Formula (I), (Ia), (II), (III), (IV), (V),(VI), (VII), (VIII), (VIIIa), (IX), (IXa) and (X) are useful for thetreatment of benign prostate hyperplasia, hirsutism, acne, adenomas andneoplasies of the prostate, benign or malignant tumor cells containingthe androgen receptor, hyperpilosity, seborrhea, endometriosis,polycystic ovary syndrome, androgenic alopecia, hypogonadism,osteoporosis, suppression of spermatogenesis, libido, cachexia,anorexia, androgen supplementation for age related decreasedtestosterone levels, prostate cancer, breast cancer, endometrial cancer,uterine cancer, hot flashes, and Kennedy's disease muscle atrophy andweakness, skin atrophy, bone loss, anemia, arteriosclerosis,cardiovascular disease, loss of energy, loss of well-being, type 2diabetes and abdominal fat accumulation. In some embodiments, a compoundof Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII),(VIIIa), (IX), (IXa) or (X) is used in the treatment of prostate cancer.In some embodiments, a compound of Formula (I), (Ia), (II), (III), (IV),(V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) are used in thetreatment of hormone-sensitive prostate cancer. In some embodiments, acompound of Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII),(VIII), (VIIIa), (IX), (IXa) or (X) is used in the treatment of hormonerefractory prostate cancer.

In one aspect, described herein are compounds of Formula (I), (Ia),(II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) and(X), pharmaceutically acceptable salts, solvates, metabolites andprodrugs thereof. In some embodiments, compounds of Formula (I), (Ia),(II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) and(X) are androgen receptor modulators. In some embodiments, the compoundof Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII),(VIIIa), (IX), (IXa) or (X) is an androgen receptor antagonist, anandrogen receptor inverse agonist, an androgen receptor degrader, anandrogen receptor trafficking modulator and/or an androgen receptorDNA-binding inhibitor. In some embodiments, the compound of Formula (I),(Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa)or (X) is an androgen receptor antagonist. In some embodiments, thecompound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII),(IX) or (X) is an androgen receptor inverse agonist. In someembodiments, the compound of Formula (I), (Ia), (II), (III), (IV), (V),(VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) is an androgen receptordegrader. In some embodiments, the compound of Formula (I), (Ia), (II),(III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) is anandrogen receptor trafficking modulator. In some embodiments, thecompound of Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII),(VIII), (VIIIa), (IX), (IXa) or (X) is an androgen receptor DNA-bindinginhibitor.

In one aspect, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, N-oxide, metabolite orprodrug thereof:

wherein,

-   -   ring A is monocyclic heteroaryl, bicyclic heteroaryl, or        naphthyl;    -   m is 0, 1, 2, 3 or 4;    -   each R^(A) is independently selected from H, halogen, —CN, —NO₂,        —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰,        —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂,        —C(═O)N(R⁹)₂, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆fluoroalkoxy, substituted or unsubstituted        C₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, substituted or        unsubstituted phenyl or substituted or unsubstituted monocyclic        heteroaryl;    -   each R¹ is independently selected from H, —OH, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆alkoxy, and substituted or unsubstituted C₁-C₆fluoroalkyl;    -   or both R¹ are taken together with the carbon atom to which they        are attached to form a substituted or unsubstituted        C₃-C₁₀cycloalkyl or a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl;    -   each R² is H; or both R² are taken together with the carbon to        which they are attached to form —C(═S)— or —C(═O)—;    -   each R³ is H; or both R³ are taken together with the carbon to        which they are attached to form —C(═S)— or —C(═O)—; provided        that each R² is not H if each R³ is H;    -   ring B is phenyl, naphthyl, monocyclic heteroaryl, or bicyclic        heteroaryl;    -   n is 0, 1, 2, 3 or 4;    -   each R⁴ is independently selected from H, halogen, —CN, —NO₂,        —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰,        —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂,        —C(═O)N(R⁹)₂, —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰,        —NR¹¹C(═O)OR¹⁰, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆fluoroalkoxy, substituted or unsubstituted        C₁-C₆alkoxy, and substituted or unsubstituted C₁-C₆heteroalkyl;    -   R⁵ is substituted or unsubstituted C₂-C₁₀alkyl, substituted or        unsubstituted C₂-C₁₀fluoroalkyl, substituted or unsubstituted        C₂-C₁₀alkoxy, substituted or unsubstituted C₂-C₁₀fluoroalkoxy,        substituted or unsubstituted C₂-C₁₀heteroalkyl, substituted or        unsubstituted C₂-C₁₀heterofluoroalkyl, or -L¹-L²-R⁶;        -   L¹ is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —C(═O)—,            —C(═O)NH—, —NHC(═O)—, —NHC(═O)O—, —NHC(═O)NH—, —C(═O)O—,            —OC(═O)—, —OC(═O)O—, —OC(═O)NH—, —NHS(═O)₂—, or —S(═O)₂NH—;        -   L² is substituted or unsubstituted C₁-C₆alkylene,            substituted or unsubstituted C₁-C₆fluoroalkylene or            substituted or unsubstituted C₁-C₆heteroalkylene;        -   R⁶ is halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,            —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,            —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂,            —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰,            —NR¹¹C(═O)OR¹⁰, substituted or unsubstituted C₁-C₆alkyl,            substituted or unsubstituted C₁-C₆fluoroalkyl, substituted            or unsubstituted C₁-C₆heteroalkyl, substituted or            unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted            monocyclic heteroaryl, substituted or unsubstituted bicyclic            heteroaryl, substituted or unsubstituted phenyl, or            substituted or unsubstituted naphthyl;    -   each R⁹ is independently selected from H, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,        substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        —C₁-C₄alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted aryl), and —C₁-C₄alkylene-(substituted or        unsubstituted heteroaryl); or    -   two R⁹ groups attached to the same N atom are taken together        with the N atom to which they are attached to form a substituted        or unsubstituted C₂-C₁₀heterocycloalkyl;    -   R¹⁰ is substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₁-C₆fluoroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted benzyl, a substituted or        unsubstituted heteroaryl, —C₁-C₄alkylene-(substituted or        unsubstituted C₃-C₁₀cycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted C₂-C₁₀heterocycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted aryl), or        —C₁-C₄alkylene-(substituted or unsubstituted heteroaryl);    -   R¹¹ is H or C₁-C₄alkyl.

For any and all of the embodiments, substituents are selected from amongfrom a subset of the listed alternatives. For example, in someembodiments, both R¹ are taken together with the carbon atom to whichthey are attached to form a substituted or unsubstitutedC₃-C₁₀cycloalkyl. In some embodiments, both R¹ are taken together withthe carbon atom to which they are attached to form a substituted orunsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclcohexyl. Insome embodiments, each R¹ is independently selected from H, —OH,C₁-C₆alkyl, and C₁-C₆fluoroalkyl. In some embodiments, each R¹ isindependently selected from H, —CH₃ and —CF₃.

In some embodiments, both R² are taken together with the carbon to whichthey are attached to form —C(═S)—; both R³ are taken together with thecarbon to which they are attached to form —C(═O)—.

In some embodiments, ring A is C-linked monocyclic heteroaryl, C-linkedbicyclic heteroaryl, or naphthyl.

In some embodiments, both R¹ are taken together with the carbon atom towhich they are attached to form a substituted or unsubstitutedC₃-C₁₀cycloalkyl; both R² are taken together with the carbon to whichthey are attached to form —C(═S)—; both R³ are taken together with thecarbon to which they are attached to form —C(═O)—; ring A isN-containing monocyclic heteroaryl, or N-containing bicyclic heteroaryl;each R^(A) is independently selected from H, halogen, —CN, —NO₂, —OH,—S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰,—CO₂R⁹, —C(═O)N(R⁹)₂, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₁-C₆fluoroalkyl, substituted orunsubstituted C₁-C₆fluoroalkoxy, substituted or unsubstitutedC₁-C₆alkoxy, substituted or unsubstituted phenyl or substituted orunsubstituted monocyclic heteroaryl.

In some embodiments, both R¹ are taken together with the carbon atom towhich they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl,or cyclohexyl; ring A is N-containing monocyclic heteroaryl selectedfrom pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl,pyrazolyl, isothiazolyl, triazolyl, and tetrazolyl.

In some embodiments, ring A is pyridinyl, pyrimidinyl, pyridazinyl, orpyrazinyl. In some embodiments, ring A is pyridinyl.

In some embodiments

In some embodiments,

In some embodiments, ring A is pyridinyl; each R^(A) is independentlyselected from H, halogen, —CN, —OH, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂,—C(═O)N(R⁹)₂, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆fluoroalkyl, substituted or unsubstitutedC₁-C₆fluoroalkoxy, substituted or unsubstituted C₁-C₆alkoxy, substitutedor unsubstituted phenyl or substituted or unsubstituted monocyclicheteroaryl.

In some embodiments, both R¹ are taken together with the carbon atom towhich they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl,or cyclohexyl; ring A is N-containing bicyclic heteroaryl selected fromquinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl,indolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl,benzothienyl, benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl,phthalazinyl, pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl,azaindolyl, pyrazolopyridinyl, thiazolopyrimidinyl, triazolopyridazinyl,thiazolopyridinyl, pyridothienyl, pyrimidiothienyl andpyrrolopyrimidinyl; each R^(A) is independently selected from H,halogen, —CN, —OH, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)N(R⁹)₂, substitutedor unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆fluoroalkoxy,substituted or unsubstituted C₁-C₆alkoxy, substituted or unsubstitutedphenyl or substituted or unsubstituted monocyclic heteroaryl.

In some embodiments, ring A is N-containing bicyclic heteroaryl selectedfrom quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,pyridopyrimidinyl, pyrazolopyrimidinyl, triazolopyridazinyl, andpyrrolopyrimidinyl.

In some embodiments, ring A is [1,2,4]triazolo[4,3-b]pyridazinyl.

In some embodiments, ring B is phenyl or monocyclic heteroaryl; each R⁴is independently selected from H, halogen, —CN, —NO₂, —OH, substitutedor unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆fluoroalkoxy,substituted or unsubstituted C₁-C₆alkoxy, and substituted orunsubstituted C₁-C₆heteroalkyl; R⁵ is substituted or unsubstitutedC₂-C₁₀alkyl, substituted or unsubstituted C₂-C₁₀fluoroalkyl, substitutedor unsubstituted C₂-C₁₀alkoxy, substituted or unsubstitutedC₂-C₁₀fluoroalkoxy, substituted or unsubstituted C₂-C₁₀heteroalkyl,substituted or unsubstituted C₂-C₁₀heterofluoroalkyl, or -L¹-L²-R⁶; L¹is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —C(═O)—, —C(═O)NH—,—NHC(═O)—, —NHS(═O)₂—, or —S(═O)₂NH—; L² is substituted or unsubstitutedC₁-C₆alkylene, substituted or unsubstituted C₁-C₆fluoroalkylene orsubstituted or unsubstituted C₁-C₆heteroalkylene; R⁶ is halogen, —CN,—NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,—CO₂R⁹, —N(R⁹)₂, —C(═O)N(R⁹)₂, substituted or unsubstitutedC₃-C₁₀cycloalkyl, substituted or unsubstituted C₂-C₁₀heterocycloalkyl,substituted or unsubstituted monocyclic heteroaryl, substituted orunsubstituted bicyclic heteroaryl, substituted or unsubstituted phenyl,or substituted or unsubstituted naphthyl.

In some embodiments, ring B is phenyl or monocyclic heteroaryl; each R⁴is independently selected from H, halogen, —CN, —NO₂, —OH, substitutedor unsubstituted C₁-C₄alkyl, substituted or unsubstitutedC₁-C₄fluoroalkyl, substituted or unsubstituted C₁-C₄fluoroalkoxy, andsubstituted or unsubstituted C₁-C₄alkoxy; R⁵ is substituted orunsubstituted C₂-C₁₀alkyl, substituted or unsubstitutedC₂-C₁₀fluoroalkyl, substituted or unsubstituted C₂-C₁₀alkoxy,substituted or unsubstituted C₂-C₁₀fluoroalkoxy, substituted orunsubstituted C₂-C₁₀heteroalkyl, substituted or unsubstitutedC₂-C₁₀heterofluoroalkyl, or -L¹-L²-R⁶; L¹ is absent, —O—, or —C(═O)NH—;L² is substituted or unsubstituted C₁-C₆alkylene, substituted orunsubstituted C₁-C₆fluoroalkylene or substituted or unsubstitutedC₁-C₆heteroalkylene; R⁶ is —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,—S(═O)₂R¹⁰, —C(═O)R¹⁰, —CO₂R⁹, —C(═O)N(R⁹)₂, substituted orunsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, substituted or unsubstituted monocyclicheteroaryl, substituted or unsubstituted bicyclic heteroaryl,substituted or unsubstituted phenyl, or substituted or unsubstitutednaphthyl.

In some embodiments, L² is substituted or unsubstituted C₁-C₆alkylene;R⁶ is —CN, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —C(═O)R¹⁰, —C(═O)N(R⁹)₂,substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted orunsubstituted C₂-C₁₀heterocycloalkyl, substituted or unsubstitutedmonocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl,substituted or unsubstituted phenyl, or substituted or unsubstitutednaphthyl.

In some embodiments, R⁶ is substituted or unsubstitutedC₃-C₁₀cycloalkyl, substituted or unsubstituted C₂-C₁₀heterocycloalkyl,substituted or unsubstituted monocyclic heteroaryl, substituted orunsubstituted bicyclic heteroaryl, substituted or unsubstituted phenyl,or substituted or unsubstituted naphthyl.

In some embodiments, L² is substituted or unsubstituted C₁-C₆alkylene;R⁶ is —CN, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —C(═O)R¹⁰, or—C(═O)N(R⁹)₂; each R⁹ is independently selected from H, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,—C₁-C₄alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),—C₁-C₄alkylene-(substituted or unsubstituted C₂-C₁₀heterocycloalkyl),—C₁-C₄alkylene-(substituted or unsubstituted aryl), and—C₁-C₄alkylene-(substituted or unsubstituted heteroaryl); or two R⁹groups attached to the same N atom are taken together with the N atom towhich they are attached to form a substituted or unsubstitutedC₂-C₁₀heterocycloalkyl; R¹⁰ is substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₁-C₆fluoroalkyl,—C₁-C₄alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),—C₁-C₄alkylene-(substituted or unsubstituted C₂-C₁₀heterocycloalkyl),—C₁-C₄alkylene-(substituted or unsubstituted aryl), or—C₁-C₄alkylene-(substituted or unsubstituted heteroaryl).

In some embodiments, provided is a compound of Formula (Ia), or apharmaceutically acceptable salt, or N-oxide thereof:

wherein,

-   -   ring A is monocyclic heteroaryl, bicyclic heteroaryl, or        naphthyl;    -   m is 1, 2, 3 or 4;    -   each R^(A) is independently H, halogen, —CN, —NO₂, —OH, —OR⁹,        —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂,        —C(═O)R¹⁰, —OC(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂, —C(═O)N(R⁹)₂,        C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, or        C₁-C₆heteroalkyl;    -   both R¹ are taken together with the carbon atom to which they        are attached to form a substituted or unsubstituted        C₃-C₆cycloalkyl or a substituted or unsubstituted        C₂-C₆heterocycloalkyl;    -   or each R¹ is independently selected from H, —OH, C₁-C₆alkyl,        C₁-C₆alkoxy, and C₁-C₆fluoroalkyl;    -   X is S or O;    -   ring B is phenyl, naphthyl, monocyclic heteroaryl, or bicyclic        heteroaryl;    -   n is 0, 1, 2, 3 or 4;    -   each R⁴ is independently selected from H, halogen, —CN, —NO₂,        —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰,        —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂,        —C(═O)N(R⁹)₂, —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰,        —NR¹¹C(═O)OR¹⁰, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy,        C₁-C₆alkoxy, and C₁-C₆heteroalkyl;    -   R⁵ is -L¹-L²-R⁶ or -L¹-R⁷;        -   L¹ is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —C(═O)—,            —C(═O)NH—, —NHC(═O)—, —NHC(═O)O—, —NHC(═O)NH—, —C(═O)O—,            —OC(═O)—, —OC(═O)O—, —OC(═O)NH—, —NHS(═O)₂—, or —S(═O)₂NH—;        -   L² is C₁-C₆alkylene, C₁-C₆fluoroalkylene or            C₁-C₆heteroalkylene;        -   R⁶ is halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,            —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,            —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂,            —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰,            —NR¹¹C(═O)OR¹⁰, C₁-C₆alkyl, C₁-C₆fluoroalkyl,            C₁-C₆heteroalkyl, substituted or unsubstituted            C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted            monocyclic heteroaryl, substituted or unsubstituted bicyclic            heteroaryl, substituted or unsubstituted phenyl, or            substituted or unsubstituted naphthyl;        -   R⁷ is substituted or unsubstituted monocyclic            C₂-C₆heterocycloalkyl, or substituted or unsubstituted            monocyclic heteroaryl;    -   each R⁹ is independently selected from H, C₁-C₆alkyl,        C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted phenyl,        substituted or unsubstituted monocyclic heteroaryl,        —C₁-C₄alkylene-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted monocyclic        C₂-C₆heterocycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted phenyl), and —C₁-C₄alkylene-(substituted or        unsubstituted monocyclic heteroaryl); or    -   two R⁹ groups attached to the same N atom are taken together        with the N atom to which they are attached to form a substituted        or unsubstituted monocyclic C₂-C₆heterocycloalkyl;    -   R¹⁰ is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, a        substituted or unsubstituted C₃-C₆cycloalkyl, a substituted or        unsubstituted monocyclic C₂-C₆heterocycloalkyl, a substituted or        unsubstituted phenyl, a substituted or unsubstituted benzyl, a        substituted or unsubstituted monocyclic heteroaryl,        —C₁-C₄alkylene-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted monocyclic        C₂-C₆heterocycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted phenyl), or —C₁-C₄alkylene-(substituted or        unsubstituted monocyclic heteroaryl);    -   R¹¹ is H or C₁-C₄alkyl.

In some embodiments, both R¹ are taken together with the carbon atom towhich they are attached to form a substituted or unsubstitutedC₃-C₆cycloalkyl; X is S; ring A is N-containing monocyclic heteroaryl;each R^(A) is independently selected from H, halogen, —CN, —NO₂, —OH,—S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰,—CO₂R⁹, —C(═O)N(R⁹)₂, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy,and C₁-C₆alkoxy; ring B is phenyl or monocyclic heteroaryl.

In some embodiments, both R¹ are taken together with the carbon atom towhich they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl,or cyclohexyl; ring A is pyridinyl, pyrimidinyl, pyridazinyl, orpyrazinyl.

In some embodiments, ring A is pyridinyl; each R^(A) is independentlyselected from H, halogen, —CN, —OH, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂,—C(═O)N(R⁹)₂, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, andC₁-C₆alkoxy.

In some embodiments, ring B is phenyl; R⁵ is -L¹-L²-R⁶; L¹ is absent,—O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —C(═O)—, —C(═O)NH—, —NHC(═O)—,—NHS(═O)₂—, or —S(═O)₂NH—; L² is C₁-C₆alkylene, C₁-C₆fluoroalkylene orC₁-C₆heteroalkylene; R⁶ is halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹,—S(═O)R¹⁰, —S(═O)₂—, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂,—C(═O)N(R⁹)₂, substituted or unsubstituted C₃-C₆cycloalkyl, substitutedor unsubstituted C₂-C₆heterocycloalkyl, substituted or unsubstitutedmonocyclic heteroaryl, or substituted or unsubstituted phenyl.

In some embodiments, ring B is phenyl; each R⁴ is independently selectedfrom H, halogen, —CN, —NO₂, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl,C₁-C₄fluoroalkoxy, and C₁-C₄alkoxy; R⁵ is -L¹-L²-R⁶; L¹ is absent, —O—,or —C(═O)NH—; L² is C₁-C₆alkylene, C₁-C₆fluoroalkylene orC₁-C₆heteroalkylene; R⁶ is —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,—S(═O)₂R¹⁰, —C(═O)R¹⁰, —CO₂R⁹, —C(═O)N(R⁹)₂, substituted orunsubstituted C₃-C₆cycloalkyl, substituted or unsubstitutedC₂-C₆heterocycloalkyl, substituted or unsubstituted monocyclicheteroaryl, or substituted or unsubstituted phenyl.

In some embodiments, L² is C₁-C₆alkylene; R⁶ is —CN, —OR⁹, —SR⁹,—S(═O)R¹⁰, —S(═O)₂R¹⁰, —C(═O)R¹⁰, —C(═O)N(R⁹)₂, substituted orunsubstituted C₃-C₆cycloalkyl, substituted or unsubstitutedC₂-C₆heterocycloalkyl, substituted or unsubstituted monocyclicheteroaryl, or substituted or unsubstituted phenyl.

In some embodiments, R⁶ is substituted or unsubstituted C₃-C₆cycloalkyl,substituted or unsubstituted C₂-C₆heterocycloalkyl, substituted orunsubstituted monocyclic heteroaryl, or substituted or unsubstitutedphenyl.

In some embodiments, L² is C₁-C₆alkylene; R⁶ is a substituted orunsubstituted C₂-C₆heterocycloalkyl.

In some embodiments, ring B is phenyl; each R⁴ is independently selectedfrom H, halogen, —CN, —NO₂, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl,C₁-C₄fluoroalkoxy, and C₁-C₄alkoxy; R⁵ is -L¹-R⁷; L¹ is absent, —O—,—S—, —S(═O)—, —S(═O)₂—, —NH—, —C(═O)—, —C(═O)NH—, —NHC(═O)—, —NHC(═O)O—,—NHC(═O)NH—, —C(═O)O—, —OC(═O)—, —OC(═O)O—, —OC(═O)NH—, —NHS(═O)₂—, or—S(═O)₂NH—; R⁷ is substituted or unsubstituted monocyclicC₂-C₆heterocycloalkyl, or substituted or unsubstituted monocyclicheteroaryl;

In some embodiments, R⁵ is -L¹-R⁷; L¹ is —O—, —S—, —S(═O)—, —S(═O)₂—,—NH—, —C(═O)—, —C(═O)NH—, or —S(═O)₂NH—; R⁷ is substituted orunsubstituted monocyclic C₂-C₆heterocycloalkyl, or substituted orunsubstituted monocyclic heteroaryl.

In some embodiments, R⁵ is -L¹-R⁷; L¹ is absent, —O—, —S—, —S(═O)—,—S(═O)₂—, —NH—, —C(═O)—, —C(═O)NH—, or —S(═O)₂NH—; R⁷ is substituted orunsubstituted monocyclic heteroaryl.

In some embodiments, the compound of Formula (I) or Formula (Ia) has thestructure of Formula (II):

In some embodiments, the compound of Formula (Ia) has the structure ofFormula (II):

-   -   wherein,

-   -   m is 2;    -   one R^(A) is —CN, —NO₂, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,        —CO₂R⁹, or —C(═O)N(R⁹)₂; and the other R^(A) is H, halogen, —OH,        C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, or C₁-C₆alkoxy;    -   n is 0 or 1;    -   each R⁴ is independently selected from H, halogen, —CN, —NO₂,        —OH, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, and        C₁-C₆alkoxy;    -   R⁵ is -L¹-L²-R⁶ or -L¹-R⁷;        -   L¹ is absent, —O—, or —C(═O)NH—;        -   L² is C₁-C₆alkylene, C₁-C₆fluoroalkylene or            C₁-C₆heteroalkylene;        -   R⁶ is —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰,            —C(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂, —C(═O)N(R⁹)₂, substituted or            unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted            C₂-C₆heterocycloalkyl, substituted or unsubstituted            monocyclic heteroaryl, or substituted or unsubstituted            phenyl;        -   R⁷ is substituted or unsubstituted monocyclic            C₂-C₆heterocycloalkyl, or substituted or unsubstituted            monocyclic heteroaryl.

In some embodiments,

one R^(A) is —CN and the other R^(A) is H, halogen, —OH, C₁-C₄alkyl,C₁-C₄fluoroalkyl, C₁-C₄fluoroalkoxy, or C₁-C₄alkoxy; each R⁴ isindependently selected from H, halogen, —OH, C₁-C₄alkyl,C₁-C₄fluoroalkyl, C₁-C₄fluoroalkoxy, and C₁-C₄alkoxy; R⁵ is -L¹-L²-R⁶ or-L¹-R⁷; L¹ is absent, —O—, or —C(═O)NH—; L² is C₁-C₆alkylene,C₁-C₆fluoroalkylene or C₁-C₆heteroalkylene; R⁶ is —CN, —NO₂, —OH, —OR⁹,—SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —C(═O)R¹⁰, —CO₂R⁹, —C(═O)N(R⁹)₂,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₆heterocycloalkyl, substituted or unsubstitutedmonocyclic heteroaryl, or substituted or unsubstituted phenyl; R⁷ issubstituted or unsubstituted monocyclic C₂-C₆heterocycloalkyl, orsubstituted or unsubstituted monocyclic heteroaryl.

In some embodiments, described herein is a a compound of Formula (I), ora pharmaceutically acceptable salt, solvate, N-oxide, metabolite orprodrug thereof:

wherein,

-   -   ring A is bicyclic heteroaryl, or naphthyl;    -   m is 0, 1, 2, or 3;    -   each R^(A) is independently selected from H, halogen, —CN, —NO₂,        —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰,        —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂,        —C(═O)N(R⁹)₂, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆fluoroalkoxy, substituted or unsubstituted        C₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, substituted or        unsubstituted phenyl or substituted or unsubstituted monocyclic        heteroaryl;    -   each R¹ is independently selected from H, —OH, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆alkoxy, and substituted or unsubstituted C₁-C₆fluoroalkyl;    -   or both R¹ are taken together with the carbon atom to which they        are attached to form a substituted or unsubstituted        C₃-C₁₀cycloalkyl or a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl;    -   each R² is H; or both R² are taken together with the carbon to        which they are attached to form—C(═S)— or —C(═O)—;    -   each R³ is H; or both R³ are taken together with the carbon to        which they are attached to form—C(═S)— or —C(═O)—; provided that        each R² is not H if each R³ is H;    -   ring B is phenyl, naphthyl, monocyclic heteroaryl, or bicyclic        heteroaryl;    -   n is 0, 1, or 2;    -   each R⁴ is independently selected from H, halogen, —CN, —NO₂,        —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰,        —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂,        —C(═O)N(R⁹)₂, —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰,        —NR¹¹C(═O)OR¹⁰, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆fluoroalkoxy, substituted or unsubstituted        C₁-C₆alkoxy, and substituted or unsubstituted C₁-C₆heteroalkyl;    -   R⁵ is H, halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,        —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,        —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂,        —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰, —NR¹¹C(═O)OR¹⁰,        substituted or unsubstituted C₁-C₁₀alkyl, substituted or        unsubstituted C₁-C₁₀fluoroalkyl, substituted or unsubstituted        C₁-C₁₀fluoroalkoxy, C₁-C₁₀alkoxy, substituted or unsubstituted        C₁-C₁₀heteroalkyl, or -L¹-L²-R⁶;        -   L¹ is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —C(═O)—,            —C(═O)NH—, —NHC(═O)—, —NHC(═O)O—, —NHC(═O)NH—, —C(═O)O—,            —OC(═O)—, —OC(═O)O—, —OC(═O)NH—, —NHS(═O)₂—, or —S(═O)₂NH—;        -   L² is substituted or unsubstituted C₁-C₆alkylene,            substituted or unsubstituted C₁-C₆fluoroalkylene or            substituted or unsubstituted C₁-C₆heteroalkylene;        -   R⁶ is halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,            —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,            —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂,            —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰,            —NR¹¹C(═O)OR¹⁰, substituted or unsubstituted C₁-C₆alkyl,            substituted or unsubstituted C₁-C₆fluoroalkyl, substituted            or unsubstituted C₁-C₆heteroalkyl, substituted or            unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted            monocyclic heteroaryl, substituted or unsubstituted bicyclic            heteroaryl, substituted or unsubstituted phenyl, or            substituted or unsubstituted naphthyl;    -   each R⁹ is independently selected from H, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,        a substituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted        or unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or        unsubstituted aryl, a substituted or unsubstituted heteroaryl,        —C₁-C₄alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted aryl), and —C₁-C₄alkylene-(substituted or        unsubstituted heteroaryl); or    -   two R⁹ groups attached to the same N atom are taken together        with the N atom to which they are attached to form a substituted        or unsubstituted C₂-C₁₀heterocycloalkyl;    -   R¹⁰ is substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₁-C₆fluoroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₄alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted aryl), or —C₁-C₄alkylene-(substituted or        unsubstituted heteroaryl);    -   R¹¹ is H or C₁-C₄alkyl.

In some embodiments, ring A is selected from quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl, indazolyl,benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothienyl,benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl, phthalazinyl,pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, azaindolyl,pyrazolopyridinyl, thiazolopyrimidinyl, triazolopyridazinyl,thiazolopyridinyl, pyridothienyl, pyrimidiothienyl, pyrrolopyrimidinyland naphthyl.

In some embodiments, ring A is selected from quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, pyridopyrimidinyl, pyrazolopyrimidinyl,triazolopyridazinyl, pyrrolopyrimidinyl, and napthyl.

In some embodiments, ring A is [1,2,4]triazolo[4,3-b]pyridazinyl.

In some embodiments, described herein is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, N-oxide, metabolite orprodrug thereof:

wherein,

-   -   ring A is a 5-membered heteroaryl;    -   m is 0, 1, 2, or 3;    -   each R^(A) is independently selected from H, halogen, —CN, —NO₂,        —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰,        —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂,        —C(═O)N(R⁹)₂, substituted or unsubstituted C₁-C₄alkyl,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆fluoroalkoxy, substituted or unsubstituted        C₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, substituted or        unsubstituted phenyl or substituted or unsubstituted monocyclic        heteroaryl;    -   each R¹ is independently selected from H, —OH, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆alkoxy, and substituted or unsubstituted C₁-C₆fluoroalkyl;    -   or both R¹ are taken together with the carbon atom to which they        are attached to form a substituted or unsubstituted        C₃-C₁₀cycloalkyl or a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl;    -   each R² is H; or both R² are taken together with the carbon to        which they are attached to form—C(═S)— or —C(═O)—;    -   each R³ is H; or both R³ are taken together with the carbon to        which they are attached to form—C(═S)— or —C(═O)—; provided that        each R² is not H if each R³ is H;    -   ring B is phenyl, naphthyl, monocyclic heteroaryl, or bicyclic        heteroaryl;    -   n is 0, 1, or 2;    -   each R⁴ is independently selected from H, halogen, —CN, —NO₂,        —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰,        —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂,        —C(═O)N(R⁹)₂, —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰,        —NR¹¹C(═O)OR¹⁰, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆fluoroalkoxy, substituted or unsubstituted        C₁-C₆alkoxy, and substituted or unsubstituted C₁-C₆heteroalkyl;    -   R⁵ is H, halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,        —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,        —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂,        —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰, —NR¹¹C(═O)OR¹⁰,        substituted or unsubstituted C₁-C₁₀alkyl, substituted or        unsubstituted C₁-C₁₀fluoroalkyl, substituted or unsubstituted        C₁-C₁₀fluoroalkoxy, substituted or unsubstituted C₁-C₁₀alkoxy,        substituted or unsubstituted C₁-C₁₀heteroalkyl, or -L¹-L²-R⁶;        -   L¹ is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —C(═O)—,            —C(═O)NH—, —NHC(═O)—, —NHC(═O)O—, —NHC(═O)NH—, —C(═O)O—,            —OC(═O)—, —OC(═O)O—, —OC(═O)NH—, —NHS(═O)₂—, or —S(═O)₂NH—;        -   L² is substituted or unsubstituted C₁-C₆alkylene,            substituted or unsubstituted C₁-C₆fluoroalkylene or            substituted or unsubstituted C₁-C₆heteroalkylene;        -   R⁶ is halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,            —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,            —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂,            —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰,            —NR¹¹C(═O)OR¹⁰, substituted or unsubstituted C₁-C₆alkyl,            substituted or unsubstituted C₁-C₆fluoroalkyl, substituted            or unsubstituted C₁-C₆heteroalkyl, substituted or            unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted            monocyclic heteroaryl, substituted or unsubstituted bicyclic            heteroaryl, substituted or unsubstituted phenyl, or            substituted or unsubstituted naphthyl;    -   each R⁹ is independently selected from H, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,        a substituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted        or unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or        unsubstituted aryl, a substituted or unsubstituted heteroaryl,        —C₁-C₄alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted aryl), and —C₁-C₄alkylene-(substituted or        unsubstituted heteroaryl); or    -   two R⁹ groups attached to the same N atom are taken together        with the N atom to which they are attached to form a substituted        or unsubstituted C₂-C₁₀heterocycloalkyl;    -   R¹⁰ is substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₁-C₆fluoroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₄alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted aryl), or —C₁-C₄alkylene-(substituted or        unsubstituted heteroaryl);    -   R¹¹ is H or C₁-C₄alkyl.

In some embodiments, ring A is selected from pyrrolyl, thiazolyl,oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, isothiazolyl,triazolyl, and tetrazolyl.

In some embodiments,

is selected from:

where X is O, S, or NR^(A). In some embodiments, X is O. In someembodiments, X is S. In some embodiments, X is NR^(A).

In some embodiments, both R¹ are taken together with the carbon atom towhich they are attached to form a C₃-C₁₀cycloalkyl; both R² are takentogether with the carbon to which they are attached to form—C(═S)—; bothR³ are taken together with the carbon to which they are attached toform-C(═O)—.

In some embodiments, the compound described herein has the structure ofFormula (III):

-   -   wherein,    -   p is 0, 1, 2, or 3.

In some embodiments, each R^(A) is independently selected from H,halogen, —CN, —NO₂, —OH, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —CO₂R⁹,—C(═O)N(R⁹)₂, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆fluoroalkyl, substituted or unsubstitutedC₁-C₆fluoroalkoxy, substituted or unsubstituted C₁-C₆alkoxy, substitutedor unsubstituted phenyl or substituted or unsubstituted monocyclicheteroaryl.

In some embodiments, each R⁴ is independently selected from H, halogen,—CN, —NO₂, —OH, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆fluoroalkyl, substituted or unsubstitutedC₁-C₆fluoroalkoxy, and substituted or unsubstituted C₁-C₆alkoxy; R⁵ issubstituted or unsubstituted C₂-C₁₀alkyl, substituted or unsubstitutedC₂-C₁₀fluoroalkyl, substituted or unsubstituted C₂-C₁₀alkoxy,substituted or unsubstituted C₂-C₁₀fluoroalkoxy, substituted orunsubstituted C₂-C₁₀heteroalkyl, substituted or unsubstitutedC₂-C₁₀heterofluoroalkyl, or -L¹-L²-R⁶; L¹ is absent, —O—, —S—, —S(═O)—,—S(═O)₂—, —NH—, —C(═O)—, —C(═O)NH—, —NHC(═O)—, —NHS(═O)₂—, or—S(═O)₂NH—; L² is substituted or unsubstituted C₁-C₆alkylene,substituted or unsubstituted C₁-C₆fluoroalkylene or substituted orunsubstituted C₁-C₆heteroalkylene; R⁶ is halogen, —CN, —NO₂, —OH, —OR⁹,—SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂,—C(═O)N(R⁹)₂, substituted or unsubstituted C₃-C₁₀cycloalkyl, substitutedor unsubstituted C₂-C₁₀heterocycloalkyl, substituted or unsubstitutedmonocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl,substituted or unsubstituted phenyl, or substituted or unsubstitutednaphthyl.

In some embodiments, each R⁴ is independently selected from H, halogen,—CN, —NO₂, —OH, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆fluoroalkyl, substituted or unsubstitutedC₁-C₆fluoroalkoxy, and substituted or unsubstituted C₁-C₆alkoxy; R⁵ isH, halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰,—S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —CO₂R⁹, —C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰,—NR¹¹C(═O)OR¹⁰, substituted or unsubstituted C₁-C₁₀alkyl, substituted orunsubstituted C₁-C₁₀fluoroalkyl, substituted or unsubstitutedC₁-C₁₀fluoroalkoxy, substituted or unsubstituted C₁-C₁₀alkoxy,substituted or unsubstituted C₁-C₁₀heteroalkyl, or -L¹-L²-R⁶, L¹ isabsent, —O—, or —C(═O)NH—; L² is C₁-C₆alkylene, C₁-C₆fluoroalkylene orC₁-C₆heteroalkylene; R⁶ is —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,—S(═O)₂R¹⁰, —C(═O)R¹⁰, —CO₂R⁹, —C(═O)N(R⁹)₂, substituted orunsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, substituted or unsubstituted monocyclicheteroaryl, substituted or unsubstituted bicyclic heteroaryl,substituted or unsubstituted phenyl, or substituted or unsubstitutednaphthyl.

In some embodiments, described herein is a compound of Formula (IV), ora pharmaceutically acceptable salt, solvate, N-oxide, metabolite orprodrug thereof:

wherein,

-   -   each R¹ is independently selected from H, —OH, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆alkoxy, and substituted or unsubstituted C₁-C₆fluoroalkyl;    -   or both R¹ are taken together with the carbon atom to which they        are attached to form a substituted or unsubstituted        C₃-C₁₀cycloalkyl or a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl;        -   X¹ is CR^(A) or N;        -   X² is CR^(A) or N;        -   X³ is CR^(A) or N; provided that at least two of X¹, X², and            X³ is CR^(A);        -   each R^(A) is independently selected from H, halogen, —CN,            —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰,            —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰,            —CO₂R⁹, —N(R⁹)₂, —C(═O)N(R⁹)₂, substituted or unsubstituted            C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,            substituted or unsubstituted C₁-C₆fluoroalkoxy, substituted            or unsubstituted C₁-C₆alkoxy, substituted or unsubstituted            C₁-C₆heteroalkyl, substituted or unsubstituted            C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted phenyl            or substituted or unsubstituted monocyclic heteroaryl;        -   ring B is phenyl, naphthyl, monocyclic heteroaryl, or            bicyclic heteroaryl;        -   n is 0, 1, or 2;        -   R⁴ is H, halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,            —S(═O)₂R¹⁰, substituted or unsubstituted C₁-C₆alkyl,            substituted or unsubstituted C₁-C₆fluoroalkyl, substituted            or unsubstituted C₁-C₆fluoroalkoxy, substituted or            unsubstituted C₁-C₆alkoxy, or substituted or unsubstituted            C₁-C₆heteroalkyl;        -   R⁵ is halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,            —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,            —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —OC(═O)N(R⁹)₂,            —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰, —NR¹¹C(═O)OR¹⁰, substituted            or unsubstituted C₂-C₁₀alkyl, substituted or unsubstituted            C₂-C₁₀fluoroalkyl, substituted or unsubstituted            C₁-C₁₀fluoroalkoxy, substituted or unsubstituted            C₁-C₁₀alkoxy, substituted or unsubstituted            C₁-C₁₀heteroalkyl, substituted or unsubstituted            C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted phenyl,            substituted or unsubstituted monocyclic heteroaryl, or            -L¹-L²-R⁶;            -   L¹ is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NH—, —C(═O)—,                —C(═O)NH—, —NHC(═O)—, —NHC(═O)O—, —NHC(═O)NH—, —C(═O)O—,                —OC(═O)—, —OC(═O)O—, —OC(═O)NH—, —NHS(═O)₂—, or                —S(═O)₂NH—;            -   L² is substituted or unsubstituted C₁-C₆alkylene,                substituted or unsubstituted C₁-C₆fluoroalkylene or                substituted or unsubstituted C₁-C₆heteroalkylene;            -   R⁶ is —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰,                —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰,                —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂, —OC(═O)N(R⁹)₂,                —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰, —NR¹¹C(═O)OR¹⁰,                substituted or unsubstituted C₃-C₁₀cycloalkyl,                substituted or unsubstituted C₂-C₁₀heterocycloalkyl,                substituted or unsubstituted monocyclic heteroaryl,                substituted or unsubstituted bicyclic heteroaryl, or                substituted or unsubstituted aryl;        -   each R⁹ is independently selected from H, substituted or            unsubstituted substituted or unsubstituted C₁-C₆heteroalkyl,            substituted or unsubstituted C₆fluoroalkyl, a substituted or            unsubstituted C₃-C₁₀cycloalkyl, a substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or            unsubstituted aryl, a substituted or unsubstituted benzyl, a            substituted or unsubstituted heteroaryl,            C₄alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),            —C₁-C₄alkylene-(substituted or unsubstituted            C₂-C₁₀heterocycloalkyl), —C₁-C₄alkylene-(substituted or            unsubstituted aryl), and —C₁-C₄alkylene-(substituted or            unsubstituted heteroaryl); or        -   two R⁹ groups attached to the same N atom are taken together            with the N atom to which they are attached to form a            substituted or unsubstituted C₂-C₁₀heterocycloalkyl;        -   R¹⁰ is substituted or unsubstituted C₁-C₆alkyl, substituted            or unsubstituted C₁-C₆heteroalkyl, substituted or            unsubstituted C₁-C₆fluoroalkyl, a substituted or            unsubstituted C₃-C₁₀cycloalkyl, a substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or            unsubstituted aryl, a substituted or unsubstituted benzyl, a            substituted or unsubstituted heteroaryl,            —C₁-C₄alkylene-(substituted or unsubstituted            C₃-C₁₀cycloalkyl), —C₁-C₄alkylene-(substituted or            unsubstituted C₂-C₁₀heterocycloalkyl),            —C₁-C₄alkylene-(substituted or unsubstituted aryl), or            —C₁-C₄alkylene-(substituted or unsubstituted heteroaryl);        -   R¹¹ is H or C₁-C₄alkyl.

In some embodiments,

m is 0, 1, 2, 3, or 4.

In some embodiments,

In some embodiments, the compound of Formula (IV) has the structure ofFormula (V):

In some embodiments, ring B is phenyl; R⁴ is H, halogen, —CN, —OH,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆fluoroalkoxy, orsubstituted or unsubstituted C₁-C₆alkoxy; R⁵ is halogen, —CN, —NO₂, —OH,—OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —CO₂R⁹,—N(R⁹)₂, substituted or unsubstituted C₂-C₁₀alkyl, substituted orunsubstituted C₂-C₁₀fluoroalkyl, substituted or unsubstitutedC₁-C₁₀fluoroalkoxy, substituted or unsubstituted C₁-C₁₀alkoxy,substituted or unsubstituted C₁-C₁₀heteroalkyl, substituted orunsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, substituted or unsubstituted phenyl, substitutedor unsubstituted monocyclic heteroaryl, or -L¹-L²-R⁶; L¹ is absent, —O—,—S—, —S(O)—, —S(O)₂—, —NH—, —C(═O)—, —C(═O)NH—, or —S(═O)₂NH—; L² issubstituted or unsubstituted C₁-C₆alkylene, substituted or unsubstitutedC₁-C₆fluoroalkylene or substituted or unsubstituted C₆heteroalkylene; R⁶is —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂,—CO₂R⁹, —C(═O)N(R⁹)₂, substituted or unsubstituted C₃-C₁₀cycloalkyl,substituted or unsubstituted C₂-C₁₀heterocycloalkyl, substituted orunsubstituted monocyclic heteroaryl, substituted or unsubstitutedbicyclic heteroaryl, or substituted or unsubstituted aryl.

In some embodiments, each R^(A) is independently selected from H,halogen, —CN, —NO₂, —OH, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —CO₂R⁹,—C(═O)N(R⁹)₂, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆fluoroalkyl, substituted or unsubstitutedC₁-C₆fluoroalkoxy, or substituted or unsubstituted C₁-C₆alkoxy.

In some embodiments, the compound of Formula (I), (Ia), (II), (IV) or(V) has the structure of Formula (VI):

In some embodiments, the compound of Formula (I), (Ia), (II), (IV) or(V) has the structure of Formula (VI):

-   -   wherein,    -   one R^(A) is —CN, —NO₂, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,        —CO₂R⁹, or —C(═O)N(R⁹)₂; and the other R^(A) is H, halogen, —OH,        C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, or C₁-C₆alkoxy;    -   both R¹ are taken together with the carbon atom to which they        are attached to form a C₃-C₆cycloalkyl;    -   or each R¹ is independently C₁-C₄alkyl;    -   R⁴ is H, halogen, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl,        C₁-C₄fluoroalkoxy, or C₁-C₄alkoxy.

In some embodiments, R⁵ is -L¹-L²-R⁶ or -L¹-R⁷; L¹ is absent, —O—, or—C(═O)NH—; L² is C₁-C₆alkylene, C₁-C₆fluoroalkylene orC₁-C₆heteroalkylene; R⁶ is —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,—S(═O)₂R¹⁰, —C(═O)R¹⁰, —CO₂R⁹, —C(═O)N(R⁹)₂, substituted orunsubstituted C₃-C₆cycloalkyl, substituted or unsubstitutedC₂-C₆heterocycloalkyl, substituted or unsubstituted monocyclicheteroaryl, or substituted or unsubstituted phenyl; R⁷ is substituted orunsubstituted monocyclic C₂-C₆heterocycloalkyl, or substituted orunsubstituted monocyclic heteroaryl.

In some embodiments, one R^(A) is —CN, —NO₂, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂,—C(═O)R¹⁰, —CO₂R⁹, —C(═O)N(R⁹)₂, substituted or unsubstituted phenyl orsubstituted or unsubstituted monocyclic heteroaryl; and the other R^(A)is H, halogen, —OH, substituted or unsubstituted C₁-C₆alkyl, substitutedor unsubstituted C₁-C₆fluoroalkyl, substituted or unsubstitutedC₁-C₆fluoroalkoxy, or substituted or unsubstituted C₁-C₆alkoxy; R⁴ is H,halogen, —CN, —OH, substituted or unsubstituted C₁-C₆alkyl, substitutedor unsubstituted C₁-C₆fluoroalkyl, substituted or unsubstitutedC₁-C₆fluoroalkoxy, or substituted or unsubstituted C₁-C₆alkoxy; R⁵ ishalogen, —CN, —NO₂, —OH, —OR⁹, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,—CO₂R⁹, substituted or unsubstituted C₂-C₁₀alkyl, substituted orunsubstituted C₂-C₁₀fluoroalkyl, substituted or unsubstitutedC₁-C₁₀fluoroalkoxy, substituted or unsubstituted C₁-C₁₀alkoxy,substituted or unsubstituted C₁-C₁₀heteroalkyl, substituted orunsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, substituted or unsubstituted phenyl, substitutedor unsubstituted monocyclic heteroaryl, or -L¹-L²-R⁶; L¹ is absent, —O—,or —C(═O)NH—; L² is substituted or unsubstituted C₁-C₆alkylene,substituted or unsubstituted C₁-C₆fluoroalkylene or substituted orunsubstituted C₁-C₆heteroalkylene; R⁶ is —CN, —NO₂, —OH, —OR⁹, —SR⁹,—S(═O)R¹⁰, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —CO₂R⁹, —C(═O)N(R⁹)₂, substitutedor unsubstituted monocyclic heteroaryl, or substituted or unsubstitutedphenyl.

In some embodiments, described herein is a compound of Formula (VII), ora pharmaceutically acceptable salt, solvate, N-oxide, metabolite orprodrug thereof:

-   -   wherein,    -   each R¹ is independently selected from H, —OH, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆alkoxy, and substituted or unsubstituted C₁-C₆fluoroalkyl;    -   or both R¹ are taken together with the carbon atom to which they        are attached to form a substituted or unsubstituted        C₃-C₁₀cycloalkyl or a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl;    -   each R^(A) is independently selected from H, halogen, —CN, —NO₂,        —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰,        —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂,        —C(═O)N(R⁹)₂, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆fluoroalkoxy, substituted or unsubstituted        C₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        phenyl or substituted or unsubstituted monocyclic heteroaryl;    -   ring B is 5-membered heteroaryl, bicyclic heteroaryl or        naphthyl;    -   n is 0, 1, or 2;    -   R⁴ is H, halogen, —CN, —NO₂, —OH, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,        substituted or unsubstituted C₁-C₆fluoroalkoxy, or substituted        or unsubstituted C₁-C₆alkoxy;    -   R⁵ is H, halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,        —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,        —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂,        —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰, —NR¹¹C(═O)OR¹⁰,        substituted or unsubstituted C₂-C₁₀alkyl, substituted or        unsubstituted C₂-C₁₀fluoroalkyl, substituted or unsubstituted        C₁-C₁₀fluoroalkoxy, substituted or unsubstituted C₁-C₁₀alkoxy,        substituted or unsubstituted C₁-C₁₀heteroalkyl, substituted or        unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted phenyl,        substituted or unsubstituted monocyclic heteroaryl, or        -L¹-L²-R⁶;        -   L¹ is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NH—, —C(═O)—,            —C(═O)NH—, —NHC(═O)—, —NHC(═O)O—, —NHC(═O)NH—, —C(═O)O—,            —OC(═O)—, —OC(═O)O—, —OC(═O)NH—, —NHS(═O)₂—, or —S(═O)₂NH—;        -   L² is substituted or unsubstituted C₁-C₆alkylene,            substituted or unsubstituted C₁-C₆fluoroalkylene or            substituted or unsubstituted C₁-C₆heteroalkylene;        -   R⁶ is halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,            —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,            —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂,            —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰,            —NR¹¹C(═O)OR¹⁰, substituted or unsubstituted            C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted            monocyclic heteroaryl, substituted or unsubstituted bicyclic            heteroaryl, or substituted or unsubstituted aryl;    -   each R⁹ is independently selected from H, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,        a substituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted        or unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or        unsubstituted aryl, a substituted or unsubstituted benzyl, a        substituted or unsubstituted heteroaryl,        —C₁-C₄alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted aryl), and —C₁-C₄alkylene-(substituted or        unsubstituted heteroaryl); or    -   two R⁹ groups attached to the same N atom are taken together        with the N atom to which they are attached to form a substituted        or unsubstituted C₂-C₁₀heterocycloalkyl;    -   R¹⁰ is substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₁-C₆fluoroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted benzyl, a substituted or        unsubstituted heteroaryl, —C₁-C₄alkylene-(substituted or        unsubstituted C₃-C₁₀cycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted C₂-C₁₀heterocycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted aryl), or        —C₁-C₄alkylene-(substituted or unsubstituted heteroaryl);    -   R¹¹ is H or C₁-C₄alkyl.

In some embodiments, described herein is a compound of Formula (VIII),or a pharmaceutically acceptable salt, solvate, N-oxide, metabolite orprodrug thereof:

wherein,

-   -   each R¹ is independently selected from H, —OH, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆alkoxy, and substituted or unsubstituted C₁-C₆fluoroalkyl;    -   or both R¹ are taken together with the carbon atom to which they        are attached to form a substituted or unsubstituted        C₃-C₆cycloalkyl or a substituted or unsubstituted        C₂-C₆heterocycloalkyl;    -   X is O or S;    -   each R^(A) is independently selected from H, halogen, —CN, —NO₂,        —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰,        —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂,        —C(═O)N(R⁹)₂, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, substituted or        unsubstituted phenyl or substituted or unsubstituted monocyclic        heteroaryl;        -   ring B is phenyl, naphthyl, monocyclic heteroaryl, or            bicyclic heteroaryl;        -   n is 0, 1, or 2;        -   R⁴ is H, halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,            —S(═O)₂R¹⁰, substituted or unsubstituted C₁-C₆alkyl,            substituted or unsubstituted C₁-C₆fluoroalkyl, substituted            or unsubstituted C₁-C₆fluoroalkoxy, substituted or            unsubstituted C₁-C₆alkoxy, or substituted or unsubstituted            C₁-C₆heteroalkyl;        -   R⁵ is halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,            —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,            —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂,            —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰,            —NR¹¹C(═O)OR¹⁰, substituted or unsubstituted C₁-C₁₀alkyl,            substituted or unsubstituted C₁-C₁₀fluoroalkyl, substituted            or unsubstituted C₁-C₁₀fluoroalkoxy, substituted or            unsubstituted C₁-C₁₀alkoxy, substituted or unsubstituted            C₁-C₁₀heteroalkyl, substituted or unsubstituted            C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted phenyl,            substituted or unsubstituted monocyclic heteroaryl, or            -L¹-L²-R⁶;            -   L¹ is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NH—, —C(═O)—,                —C(═O)NH—, —NHC(═O)—, —NHC(═O)O—, —NHC(═O)NH—, —C(═O)O—,                —OC(═O)—, —OC(═O)O—, —OC(═O)NH—, —NHS(═O)₂—, or                —S(═O)₂NH—;            -   L² is substituted or unsubstituted C₁-C₆alkylene,                substituted or unsubstituted C₁-C₆fluoroalkylene or                substituted or unsubstituted C₁-C₆heteroalkylene;            -   R⁶ is —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰,                —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰,                —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂, —OC(═O)N(R⁹)₂,                —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰, —NR¹¹C(═O)OR¹⁰,                substituted or unsubstituted C₃-C₁₀cycloalkyl,                substituted or unsubstituted C₂-C₁₀heterocycloalkyl,                substituted or unsubstituted monocyclic heteroaryl,                substituted or unsubstituted bicyclic heteroaryl, or                substituted or unsubstituted aryl;        -   each R⁹ is independently selected from H, substituted or            unsubstituted C₁-C₆alkyl, substituted or unsubstituted            C₁-C₆heteroalkyl, substituted or unsubstituted            C₁-C₆fluoroalkyl, a substituted or unsubstituted            C₃-C₁₀cycloalkyl, a substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl,            a substituted or unsubstituted benzyl, a substituted or            unsubstituted heteroaryl, —C₁-C₄alkylene-(substituted or            unsubstituted C₃-C₁₀cycloalkyl), —C₁-C₄alkylene-(substituted            or unsubstituted C₂-C₁₀heterocycloalkyl),            —C₁-C₄alkylene-(substituted or unsubstituted aryl), and            —C₁-C₄alkylene-(substituted or unsubstituted heteroaryl); or        -   two R⁹ groups attached to the same N atom are taken together            with the N atom to which they are attached to form a            substituted or unsubstituted C₂-C₁₀heterocycloalkyl;        -   R¹⁰ is substituted or unsubstituted C₁-C₆alkyl, substituted            or unsubstituted C₁-C₆heteroalkyl, substituted or            unsubstituted C₁-C₆fluoroalkyl, a substituted or            unsubstituted C₃-C₁₀cycloalkyl, a substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or            unsubstituted aryl, a substituted or unsubstituted benzyl, a            substituted or unsubstituted heteroaryl,            —C₁-C₄alkylene-(substituted or unsubstituted            C₃-C₁₀cycloalkyl), —C₁-C₄alkylene-(substituted or            unsubstituted C₂-C₁₀heterocycloalkyl),            —C₁-C₄alkylene-(substituted or unsubstituted aryl), or            —C₁-C₄alkylene-(substituted or unsubstituted heteroaryl);        -   R¹¹ is H or C₁-C₄alkyl.

In some embodiments, X is S; ring B is phenyl; R⁴ is H, halogen, —CN,—OH, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, or C₁-C₆alkoxy; R⁵is halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰,—S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂, —C(═O)N(R⁹)₂, substituted orunsubstituted C₁-C₁₀alkyl, substituted or unsubstitutedC₁-C₁₀fluoroalkyl, substituted or unsubstituted C₁-C₁₀fluoroalkoxy,substituted or unsubstituted C₁-C₁₀alkoxy, substituted or unsubstitutedC₁-C₁₀heteroalkyl, substituted or unsubstituted C₃-C₁₀cycloalkyl,substituted or unsubstituted C₂-C₁₀heterocycloalkyl, substituted orunsubstituted phenyl, substituted or unsubstituted monocyclicheteroaryl, or -L¹-L²-R⁶; L¹ is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NH—,—C(═O)—, —C(═O)NH—, or —S(═O)₂NH—; L² is substituted or unsubstitutedC₁-C₆alkylene, substituted or unsubstituted C₁-C₆fluoroalkylene orsubstituted or unsubstituted C₁-C₆heteroalkylene; R⁶ is —CN, —NO₂, —OH,—OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —CO₂R⁹, —C(═O)N(R⁹)₂,substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted orunsubstituted C₂-C₁₀heterocycloalkyl, substituted or unsubstitutedmonocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl,or substituted or unsubstituted aryl.

In some embodiments, each R^(A) is independently selected from H,halogen, —CN, —NO₂, —OH, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —CO₂R⁹,—C(═O)N(R⁹)₂, C₁-C₆alkyl, and C₆alkoxy.

In some embodiments, described herein is a compound of Formula (VIIIa),or a pharmaceutically acceptable salt, or N-oxide thereof:

-   -   wherein,    -   both R¹ are taken together with the carbon atom to which they        are attached to form a substituted or unsubstituted        C₃-C₆cycloalkyl or a substituted or unsubstituted        C₂-C₆heterocycloalkyl;    -   or    -   each R¹ is independently H, —OH, C₁-C₆alkyl, C₁-C₆alkoxy, or        C₁-C₆fluoroalkyl;    -   X is O or S;    -   R^(A) is C₁-C₆alkyl;    -   ring B is phenyl, naphthyl, monocyclic heteroaryl, or bicyclic        heteroaryl;    -   n is 0, 1, or 2;    -   R⁴ is H, halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,        —S(═O)₂R¹⁰, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy,        C₁-C₆alkoxy, or C₁-C₆heteroalkyl;    -   R⁵ is halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,        —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,        —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂,        —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰, —NR¹¹C(═O)OR¹⁰,        C₁-C₁₀alkyl, C₁-C₁₀fluoroalkyl, C₁-C₁₀fluoroalkoxy,        C₁-C₁₀alkoxy, C₁-C₁₀heteroalkyl, substituted or unsubstituted        C₃-C₁₀cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted phenyl,        substituted or unsubstituted monocyclic heteroaryl, or        -L¹-L²-R⁶;        -   L¹ is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NH—, —C(═O)—,            —C(═O)NH—, —NHC(═O)—, —NHC(═O)O—, —NHC(═O)NH—, —C(═O)O—,            —OC(═O)—, —OC(═O)O—, —OC(═O)NH—, —NHS(═O)₂—, or —S(═O)₂NH—;        -   L² is C₁-C₆alkylene, C₁-C₆fluoroalkylene or            C₁-C₆heteroalkylene;        -   R⁶ is —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰,            —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰,            —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂, —OC(═O)N(R⁹)₂,            —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰, —NR¹¹C(═O)OR¹⁰, substituted            or unsubstituted C₃-C₁₀cycloalkyl, substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, substituted or            unsubstituted monocyclic heteroaryl, substituted or            unsubstituted bicyclic heteroaryl, or substituted or            unsubstituted aryl;    -   each R⁹ is independently selected from H, C₁-C₆alkyl,        C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, a substituted or        unsubstituted C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted benzyl, a substituted or        unsubstituted heteroaryl, —C₁-C₄alkylene-(substituted or        unsubstituted C₃-C₁₀cycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted C₂-C₁₀heterocycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted aryl), and        —C₁-C₄alkylene-(substituted or unsubstituted heteroaryl); or    -   two R⁹ groups attached to the same N atom are taken together        with the N atom to which they are attached to form a substituted        or unsubstituted C₂-C₁₀heterocycloalkyl;    -   R¹⁰ is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, a        substituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or        unsubstituted aryl, a substituted or unsubstituted benzyl, a        substituted or unsubstituted heteroaryl,        —C₁-C₄alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted aryl), or —C₁-C₄alkylene-(substituted or        unsubstituted heteroaryl);    -   R¹¹ is H or C₁-C₄alkyl.

In some embodiments, X is S; ring B is phenyl; R⁴ is H, halogen, —CN,—OH, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, or C₁-C₆alkoxy; R⁵is halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰,—S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂, —C(═O)N(R⁹)₂, C₁-C₁₀alkyl,C₁-C₁₀fluoroalkyl, C₁-C₁₀fluoroalkoxy, C₁-C₁₀alkoxy, C₁-C₁₀heteroalkyl,substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted orunsubstituted C₂-C₁₀heterocycloalkyl, substituted or unsubstitutedphenyl, substituted or unsubstituted monocyclic heteroaryl, or-L¹-L²-R⁶, L¹ is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NH—, —C(═O)—,—C(═O)NH—, or —S(═O)₂NH—; L² is C₁-C₆alkylene, C₁-C₆fluoroalkylene orC₁-C₆heteroalkylene; R⁶ is —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,—S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —CO₂R⁹, —C(═O)N(R⁹)₂, substituted orunsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, substituted or unsubstituted monocyclicheteroaryl, substituted or unsubstituted bicyclic heteroaryl, orsubstituted or unsubstituted aryl.

In some embodiments, R^(A) is C₁-C₆alkyl; both R¹ are taken togetherwith the carbon atom to which they are attached to form aC₃-C₆cycloalkyl; or each R¹ is independently C₁-C₄alkyl.

In some embodiments, the compound of Formula (VIII) has the structure ofFormula (IX):

In some embodiments, each R^(A) is independently selected from H,halogen, —OH, C₁-C₆alkyl, and C₁-C₆alkoxy.

In some embodiments, the compound of Formula (VIII) or Formula (VIIIa)has the structure of Formula (IXa):

In some embodiments, each R⁹ is independently selected from H,C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, a substituted orunsubstituted C₃-C₆cycloalkyl, a substituted or unsubstitutedC₂-C₆heterocycloalkyl, a substituted or unsubstituted phenyl, asubstituted or unsubstituted benzyl, and a substituted or unsubstitutedmonocyclic heteroaryl; or two R⁹ groups attached to the same N atom aretaken together with the N atom to which they are attached to form asubstituted or unsubstituted C₂-C₆heterocycloalkyl; R¹⁰ is C₁-C₆alkyl,C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, a substituted or unsubstitutedC₃-C₆cycloalkyl, a substituted or unsubstituted C₂-C₆heterocycloalkyl, asubstituted or unsubstituted phenyl, or a substituted or unsubstitutedmonocyclic heteroaryl.

In some embodiments, R⁵ is halogen, —CN, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,—S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂, —C(═O)NH(R⁹),C₁-C₁₀alkyl, C₁-C₁₀fluoroalkyl, C₁-C₁₀fluoroalkoxy, C₁-C₁₀alkoxy,C₁-C₁₀heteroalkyl, substituted or unsubstituted C₃-C₁₀cycloalkyl,substituted or unsubstituted C₂-C₁₀heterocycloalkyl, substituted orunsubstituted phenyl, substituted or unsubstituted monocyclicheteroaryl, or -L¹-L²-R⁶; L¹ is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NH—,—C(═O)—, —C(═O)NH—, or —S(═O)₂NH—; L² is C₁-C₆alkylene; R⁶ is —CN, —OH,—OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —CO₂R⁹, —C(═O)N(R⁹)₂,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₆heterocycloalkyl, substituted or unsubstitutedmonocyclic heteroaryl, or substituted or unsubstituted phenyl.

In some embodiments, R^(A) is —CH₃; both R¹ are taken together with thecarbon atom to which they are attached to form a cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl; or each R¹ is —CH₃; R⁵ ishalogen, —CN, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂,—C(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂, —C(═O)NH(R⁹), C₁-C₁₀alkyl,C₁-C₁₀fluoroalkyl, C₁-C₁₀fluoroalkoxy, C₁-C₁₀alkoxy, C₁-C₁₀heteroalkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₆heterocycloalkyl, substituted or unsubstitutedphenyl, substituted or unsubstituted monocyclic heteroaryl, or-L¹-L²-R⁶; L¹ is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NH—, —C(═O)—,—C(═O)NH—, or —S(═O)₂NH—; L² is C₁-C₆alkylene; R⁶ is substituted orunsubstituted C₂-C₆heterocycloalkyl, substituted or unsubstitutedmonocyclic heteroaryl, or substituted or unsubstituted phenyl.

In some embodiments, described herein is a compound of Formula (X), or apharmaceutically acceptable salt, solvate, N-oxide, metabolite orprodrug thereof:

-   -   wherein,    -   each R¹ is independently selected from H and —CH₃;    -   or both R¹ are taken together with the carbon atom to which they        are attached to form a cyclobutyl;    -   X is O or S;    -   X¹ is CH or N;    -   R^(A) is —CN or —C(═O)NH₂;    -   R⁵ is —CO₂H, or —C(═O)NH₂.

In some embodiments, described herein is a compound of Formula (X), or apharmaceutically acceptable salt, solvate, N-oxide, metabolite orprodrug thereof:

-   -   wherein,    -   each R¹ is independently selected from H and —CH₃;    -   or both R¹ are taken together with the carbon atom to which they        are attached to form a cyclobutyl;    -   X is O;    -   X¹ is CH or N;    -   R^(A) is —CN or —C(═O)NH₂;    -   R⁵ is —CO₂H, —C(═O)NH₂ or —C(═O)NH(CH₃).

In some embodiments, described herein is a compound of Formula (X), or apharmaceutically acceptable salt, solvate, N-oxide, metabolite orprodrug thereof:

-   -   wherein,    -   each R¹ is independently selected from H and —CH₃;    -   or both R¹ are taken together with the carbon atom to which they        are attached to form a cyclobutyl;    -   X is O or S;    -   X¹ is CH or N;    -   R^(A) is —C(═O)NH₂;    -   R⁵ is —CO₂H, —C(═O)NH₂ or —C(═O)NH(CH₃).

Throughout the specification, groups and substituents thereof can bechosen by one skilled in the field to provide stable moieties andcompounds.

Compounds disclosed herein are selective androgen receptor modulators.In some embodiments, compounds disclosed herein have high specificityfor the androgen receptor and have desirable, tissue-selectivepharmacological activities. Desirable, tissue-selective pharmacologicalactivities include, but are not limited to, AR antagonist activity inprostate cells and no AR antagonist activity in non-prostrate cells. Insome embodiments, compounds disclosed herein are antiandrogens thatdisplay negligible or no AR agonist activity.

In some embodiments, presented herein are compounds selected from activemetabolites, tautomers, pharmaceutically acceptable solvates,pharmaceutically acceptable salts or prodrugs of a compound of Formula(I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX),(IXa) or (X).

In some embodiments, provided is a pharmaceutical composition comprisinga therapeutically effective amount of a compound of Formula (I), (Ia),(II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or(X). In some embodiments, the pharmaceutical composition also containsat least one pharmaceutically acceptable inactive ingredient. In someembodiments, the pharmaceutical composition is formulated forintravenous injection, subcutaneous injection, oral administration, ortopical administration. In some embodiments, the pharmaceuticalcomposition is a tablet, a pill, a capsule, a liquid, a suspension, agel, a colloid, a dispersion, a suspension, a solution, an emulsion, anointment, or a lotion.

In some embodiments, the pharmaceutical composition further comprisesone or more additional therapeutically active agents selected from:corticosteroids, anti-emetic agents, analgesics, anti-cancer agents,anti-inflammatories, kinase inhibitors, HSP90 inhibitors, histonedeacetylase (HDAC) inhibitors.

In some embodiments, provided is a method comprising administering acompound of Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII),(VIII), (VIIIa), (IX), (IXa) or (X) to a human with a diseases orcondition that is androgen receptor meditated or androgen receptordependent. In some embodiments, the human is already being administeredone or more additional therapeutically active agents other than acompound of Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII),(VIII), (VIIIa), (IX), (IXa) or (X). In some embodiments, the methodfurther comprises administering one or more additional therapeuticallyactive agents other than a compound of Formula (I), (Ia), (II), (III),(IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X).

In some embodiments, the one or more additional therapeutically activeagents other than a compound of Formula (I), (Ia), (II), (III), (IV),(V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) are selected from:corticosteroids, anti-emetic agents, analgesics, anti-cancer agents,anti-inflammatories, kinase inhibitors, HSP90 inhibitors, histonedeacetylase (HDAC) inhibitors.

In some embodiments, described herein is a method of treating anandrogen receptor dependent or androgen receptor mediated disease orcondition in mammal comprising administering to the mammal atherapeutically effective amount of a compound of Formula (I), (Ia),(II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or(X), or a pharmaceutically acceptable salt thereof or N-oxide thereof.In some embodiments, the adrogen receptor dependent or androgen receptormediated disease or condition is benign prostate hyperplasia, hirsutism,acne, adenomas and neoplasies of the prostate, benign or malignant tumorcells containing the androgen receptor, hyperpilosity, seborrhea,endometriosis, polycystic ovary syndrome, androgenic alopecia,hypogonadism, osteoporosis, suppression of spermatogenesis, libido,cachexia, anorexia, androgen supplementation for age related decreasedtestosterone levels, prostate cancer, breast cancer, endometrial cancer,uterine cancer, hot flashes, and Kennedy's disease muscle atrophy andweakness, skin atrophy, bone loss, anemia, arteriosclerosis,cardiovascular disease, loss of energy, loss of well-being, type 2diabetes or abdominal fat accumulation.

In some embodiments, described herein is a method of treating cancer ina mammal comprising administering to the mammal a therapeuticallyeffective amount of a compound of Formula (I), (Ia), (II), (III), (IV),(V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X), or apharmaceutically acceptable salt thereof or N-oxide thereof. In someembodiments, the cancer is a hormone dependent cancer. In someembodiments, the hormone dependent cancer is an androgen receptordependent cancer. In some embodiments, the cancer is prostate cancer. Insome embodiments, the cancer is hormone refractory prostate cancer. Insome embodiments, the method of treating cancer further comprisesadministering to the mammal at least one additional anti-cancer agent.

In some embodiments, described herein is a method of treating cancer ina mammal comprising administering to the mammal a therapeuticallyeffective amount of a compound, wherein the compound is: an androgenreceptor inverse agonist; androgen receptor antagonist; androgenreceptor degrader; androgen receptor trafficking modulator; androgenreceptor degrader; androgen receptor DNA-binding inhibitor; orcombinations thereof. In some embodiments, the cancer is prostatecancer. In some embodiments, the cancer is hormone refractory prostatecancer. In some embodiments, the compound is a compound of Formula (I),(Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa)or (X), or a pharmaceutically acceptable salt thereof or N-oxidethereof.

Pharmaceutical formulations described herein are administrable to asubject in a variety of ways by multiple administration routes,including but not limited to, oral, parenteral (e.g., intravenous,subcutaneous, intramuscular), buccal, topical or transdermaladministration routes. The pharmaceutical formulations described hereininclude, but are not limited to, aqueous liquid dispersions,self-emulsifying dispersions, solid solutions, liposomal dispersions,solid dosage forms, powders, immediate release formulations, controlledrelease formulations, fast melt formulations, tablets, capsules, pills,delayed release formulations, extended release formulations, pulsatilerelease formulations, multiparticulate formulations, and mixed immediateand controlled release formulations.

In some embodiments, the compounds of Formula (I), (Ia), (II), (III),(IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) and (X) areadministered orally.

In some embodiments, the compounds of Formula (I), (Ia), (II), (III),(IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) and (X) areadministered topically. In such embodiments, the compound of Formula(I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX),(IXa) or (X) is formulated into a variety of topically administrablecompositions, such as solutions, suspensions, lotions, gels, pastes,shampoos, scrubs, rubs, smears, medicated sticks, medicated bandages,balms, creams or ointments. Such pharmaceutical compounds can containsolubilizers, stabilizers, tonicity enhancing agents, buffers andpreservatives. In one aspect, the compounds of Formula (I), (Ia), (II),(III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) and (X) areadministered topically to the skin.

In another aspect is the use of a compound of Formula (I), (Ia), (II),(III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) inthe manufacture of a medicament for treating a disease, disorder orconditions in which the activity of androgen receptors contributes tothe pathology and/or symptoms of the disease or condition. In oneaspect, the disease or condition is any of the diseases or conditionsspecified herein.

In any of the aforementioned aspects are further embodiments in which:(a) the effective amount of the compound of Formula (I), (II), (III),(IV), (V), (VI), (VII), (VIII), (IX) or (X) is systemically administeredto the mammal; and/or (b) the effective amount of the compound isadministered orally to the mammal; and/or (c) the effective amount ofthe compound is intravenously administered to the mammal; and/or (d) theeffective amount of the compound is administered by injection to themammal; and/or (e) the effective amount of the compound is administeredtopically to the mammal; and/or (f) the effective amount is adminsterednon-systemically or locally to the mammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce; (ii) the compound is administered to the mammal multiple timesover the span of one day; (iii) continually; or (iv) continuously.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredcontinuously or intermittently: as in a a single dose; (ii) the timebetween multiple administrations is every 6 hours; (iii) the compound isadministered to the mammal every 8 hours; (iv) the compound isadministered to the mammal every 12 hours; (v) the compound isadministered to the mammal every 24 hours. In further or alternativeembodiments, the method comprises a drug holiday, wherein theadministration of the compound is temporarily suspended or the dose ofthe compound being administered is temporarily reduced; at the end ofthe drug holiday, dosing of the compound is resumed. In one embodiment,the length of the drug holiday varies from 2 days to 1 year.

Also provided is a method of reducing AR activation in a mammalcomprising administering to the mammal at least one compound having thestructure of Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII),(VIII), (VIIIa), (IX), (IXa) or (X). In some embodiments, the methodcomprises reducing AR activation in prostate cells in the mammal. Insome embodiments, the method comprises reducing AR activation inprostate cells in the mammal and not in non-prostrate cells. In someembodiments, the method of reducing AR activation comprises reducing thebinding of androgens to the androgen receptor. In some embodiments, themethod of reducing AR activation comprises reducing AR concentrations.

In some cases disclosed herein is the use of a compound of Formula (I),(Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa)or (X) in the manufacture of a medicament for the treatment of diseasesor conditions that are androgen receptor dependent or androgen receptormediated. In some embodiments, the disease or condition is prostratecancer. In some embodiments, the androgen receptor dependent or androgenreceptor mediated disease or condition is described herein.

In some cases disclosed herein is the use of a compound of Formula (I),(Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa)or (X) in the treatment or prevention of diseases or conditions that areandrogen receptor dependent or androgen receptor mediated. In someembodiments, the androgen receptor dependent or androgen receptormediated disease or condition is described herein.

In any of the embodiments disclosed herein, the mammal is a human.

In some embodiments, compounds provided herein are administered to ahuman.

In some embodiments, compounds provided herein are orally administered.

In some embodiments, compounds provided herein are used to diminish,reduce, or eliminate the activity of androgen receptors.

Articles of manufacture, which include packaging material, a compound ofFormula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa),(IX), (IXa) or (X) within the packaging material, and a label thatindicates that the compound or composition, or pharmaceuticallyacceptable salt, tautomers, pharmaceutically acceptable N-oxide,pharmaceutically active metabolite, pharmaceutically acceptable prodrug,or pharmaceutically acceptable solvate thereof, is used for reducing,diminishing or eliminating the effects of androgen receptors, or for thetreatment, prevention or amelioration of one or more symptoms of adisease or condition that would benefit from a reduction or eliminationof androgen receptor activity, are provided.

Other objects, features and advantages of the compounds, methods andcompositions described herein will become apparent from the followingdetailed description. It should be understood, however, that thedetailed description and the specific examples, while indicatingspecific embodiments, are given by way of illustration only, sincevarious changes and modifications within the spirit and scope of theinstant disclosure will become apparent to those skilled in the art fromthis detailed description

DETAILED DESCRIPTION OF THE INVENTION

Androgen receptor (AR) is a member of the steroid and nuclear receptorsuperfamily. Among this large family of proteins, only five vertebratesteroid receptors are known and include the androgen receptor, estrogenreceptor, progesterone receptor, glucocorticoid receptor, andmineralocorticoid receptor. AR is a soluble protein that functions as anintracellular transcriptional factor. AR function is regulated by thebinding of androgens, which initiates sequential conformational changesof the receptor that affect receptor—protein interactions andreceptor—DNA interactions.

AR is mainly expressed in androgen target tissues, such as the prostate,skeletal muscle, liver, and central nervous system (CNS), with thehighest expression level observed in the prostate, adrenal gland, andepididymis. AR can be activated by the binding of endogenous androgens,including testosterone and 5α-dihydrotestosterone (5α-DHT).

The androgen receptor (AR), located on Xq11-12, is a 110 kD nuclearreceptor that, upon activation by androgens, mediates transcription oftarget genes that modulate growth and differentiation of prostateepithelial cells Similar to the other steroid receptors, unbound AR ismainly located in the cytoplasm and associated with a complex of heatshock proteins (HSPs) through interactions with the ligand-bindingdomain. Upon agonist binding, AR goes through a series of conformationalchanges: the heat shock proteins dissociate from AR, and the transformedAR undergoes dimerization, phosphorylation, and translocation to thenucleus, which is mediated by the nuclear localization signal.Translocated receptor then binds to the androgen response element (ARE),which is characterized by the six-nucleotide half-site consensussequence 5′-TGTTCT-3′ spaced by three random nucleotides and is locatedin the promoter or enhancer region of AR gene targets. Recruitment ofother transcription co-regulators (including co-activators andco-repressors) and transcriptional machinery further ensures thetransactivation of AR-regulated gene expression. All of these processesare initiated by the ligand-induced conformational changes in theligand-binding domain.

AR signaling is crucial for the development and maintenance of malereproductive organs including the prostate gland, as genetic malesharboring loss of function AR mutations and mice engineered with ARdefects do not develop prostates or prostate cancer. This dependence ofprostate cells on AR signaling continues even upon neoplastictransformation. Androgen depletion (now using GnRH agonists) continuesto be the mainstay of prostate cancer treatment. However androgendepletion is usually effective for a limited duration and prostatecancer evolves to regain the ability to grow despite low levels ofcirculating androgens.

Treatment options for castration resistant prostate cancer (CRPC) are anunmet need with docetaxel being the only agent that has been shown toprolong survival. Interestingly, while a small minority of CRPC doesbypass the requirement for AR signaling, the vast majority of CRPC,though frequently termed “androgen independent prostate cancer” or“hormone refractory prostate cancer,” retains its lineage dependence onAR signaling.

Prostate cancer is the second most common cause of cancer death in menin the US, and approximately one in every six American men will bediagnosed with the disease during his lifetime. Treatment aimed ateradicating the tumor is unsuccessful in 30% of men, who developrecurrent disease that is usually manifest first as a rise in plasmaprostate-specific antigen (PSA) followed by spread to distant sites.Given that prostate cancer cells depend on androgen receptor (AR) fortheir proliferation and survival, these men are treated with agents thatblock production of testosterone (e.g. GnRH agonists), alone or incombination with anti-androgens (e.g. bicalutamide), which antagonizethe effect of any residual testosterone. The approach is effective asevidenced by a drop in PSA and regression of visible tumor (if present);however, this is followed by regrowth as a “castration resistant”prostate cancer (CRPC) to which most patients eventually succumb. Recentstudies on the molecular basis of CRPC have demonstrated that CRPCcontinues to depend on AR signaling and that a key mechanism of acquiredresistance is an elevated level of AR protein (Nat. Med, 2004, 10,33-39). AR targeting agents with activity in hormone sensitive andcastration resistant resistant prostate cancer have great promise intreating this lethal disease.

Anti-androgens are useful for the treatment of prostate cancer duringits early stages. However, prostate cancer often advances to ahormone-refractory state in which the disease progresses in the presenceof continued androgen ablation or anti-androgen therapy. Instances ofantiandrogen withdrawal syndrome have also been reported after prolongedtreatment with anti-androgens. Antiandrogen withdrawal syndrome iscommonly observed clinically and is defined in terms of the tumorregression or symptomatic relief observed upon cessation of antiandrogentherapy. AR mutations that result in receptor promiscuity and theability of these anti-androgens to exhibit agonist activity might atleast partially account for this phenomenon. For example,hydroxyflutamide and bicalutamide act as AR agonists in T877A andW741L/W741C AR mutants, respectively.

In the setting of prostate cancer cells that were rendered “castrationresistant” via overexpression of AR, it has been demonstrated thatcertain anti-androgen compounds, such as bicalutamide, have noantagonist activity, but instead have modest agonist activity (Science,2009 May 8; 324(5928): 787-90). This agonist activity helps to explain aclinical observation, called the anti-androgen withdrawal syndrome,whereby about 30% of men who progress on AR antagonists experience adecrease in serum PSA when therapy is discontinued (J Clin Oncol, 1993.11(8): p. 1566-72).

Given the central role of AR in prostate cancer development andprogression, compounds disclosed herein are useful in the treatment ofprostrate cancer, either alone or in combination with other agent agentsthat can modulate other critical pathways in prostate cancer, includingbut not limited to those that target IGF1R, the PI3K/AKT/mTOR axis,HSP90, or histone deacetylases.

AR-related diseases or conditions include, but are not limited to,benign prostate hyperplasia, hirsutism, acne, adenomas and neoplasies ofthe prostate, benign or malignant tumor cells containing the androgenreceptor, hyperpilosity, seborrhea, endometriosis, polycystic ovarysyndrome, androgenic alopecia, hypogonadism, osteoporosis, suppressionof spermatogenesis, libido, cachexia, anorexia, androgen supplementationfor age related decreased testosterone levels, prostate cancer, breastcancer, endometrial cancer, uterine cancer, hot flashes, and Kennedy'sdisease muscle atrophy and weakness, skin atrophy, bone loss, anemia,arteriosclerosis, cardiovascular disease, loss of energy, loss ofwell-being, type 2 diabetes and abdominal fat accumulation.

In some embodiments, compounds disclosed herein inhibit AR nucleartranslocation, DNA binding to androgen response elements, andcoactivator recruitment. In some embodiments, compounds disclosed hereinexhibit no agonist activity in AR-overexpressing prostate cancer cells.

In some embodiments, compounds disclosed herein are used to treatprostrate cancer in a mammal, wherein the mammal is chemotherapy-nave.

In some embodiments, compounds disclosed herein are used to treatprostrate cancer in a mammal, wherein the mammal is being treated forprostrate cancer with at least one anti-cancer agent. In one embodiment,the prostrate cancer is hormone refractory prostate cancer. In oneembodiment, the prostrate cancer is bicalutamide-resistant prostatecancer.

Compounds

Compounds of Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII),(VIII), (VIIIa), (IX), (IXa) and (X), including pharmaceuticallyacceptable salts, prodrugs, and pharmaceutically acceptable solvatesthereof, are androgen receptor modulators, such as, for example, ARinverse agonists, AR antagonists, AR degraders, AR traffickingmodulators and/or AR DNA-binding inhibitors, and are useful in thetreatment of androgen receptor-dependent or androgen receptor-mediatedconditions or diseases of diseases or conditions.

In one aspect, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, N-oxide, metabolite orprodrug thereof:

wherein,

-   -   ring A is monocyclic heteroaryl, bicyclic heteroaryl, or        naphthyl;    -   m is 0, 1, 2, 3 or 4;    -   each R^(A) is independently selected from H, halogen, —CN, —NO₂,        —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰,        —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂,        —C(═O)N(R⁹)₂, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆fluoroalkoxy, substituted or unsubstituted        C₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, substituted or        unsubstituted phenyl or substituted or unsubstituted monocyclic        heteroaryl;    -   each R¹ is independently selected from H, —OH, substituted or        unsubstituted substituted or unsubstituted C₁-C₆alkoxy, and        substituted or unsubstituted C₁-C₆fluoroalkyl;    -   or both R¹ are taken together with the carbon atom to which they        are attached to form a substituted or unsubstituted        C₃-C₁₀cycloalkyl or a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl;    -   each R² is H; or both R² are taken together with the carbon to        which they are attached to form—C(═S)— or —C(═O)—;    -   each R³ is H; or both R³ are taken together with the carbon to        which they are attached to form—C(═S)— or —C(═O)—; provided that        each R² is not H if each R³ is H;    -   ring B is phenyl, naphthyl, monocyclic heteroaryl, or bicyclic        heteroaryl;    -   n is 0, 1, 2, 3 or 4;    -   each R⁴ is independently selected from H, halogen, —CN, —NO₂,        —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰,        —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂,        —C(═O)N(R⁹)₂, —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰,        —NR¹¹C(═O)OR¹⁰, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆fluoroalkoxy, substituted or unsubstituted        C₁-C₆alkoxy, and substituted or unsubstituted C₁-C₆heteroalkyl;    -   R⁵ is substituted or unsubstituted C₂-C₁₀alkyl, substituted or        unsubstituted C₂-C₁₀fluoroalkyl, substituted or unsubstituted        C₂-C₁₀alkoxy, substituted or unsubstituted C₂-C₁₀fluoroalkoxy,        substituted or unsubstituted C₂-C₁₀heteroalkyl, substituted or        unsubstituted C₂-C₁₀heterofluoroalkyl, or -L¹-L²-R⁶;        -   L¹ is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —C(═O)—,            —C(═O)NH—, —NHC(═O)—, —NHC(═O)O—, —NHC(═O)NH—, —C(═O)O—,            —OC(═O)—, —OC(═O)O—, —OC(═O)NH—, —NHS(═O)₂—, or —S(═O)₂NH—;        -   L² is substituted or unsubstituted C₁-C₆alkylene,            substituted or unsubstituted C₁-C₆fluoroalkylene or            substituted or unsubstituted C₁-C₆heteroalkylene;        -   R⁶ is halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,            —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,            —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂,            —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰,            —NR¹¹C(═O)OR¹⁰, substituted or unsubstituted C₁-C₆alkyl,            substituted or unsubstituted C₁-C₆fluoroalkyl, substituted            or unsubstituted C₁-C₆heteroalkyl, substituted or            unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted            monocyclic heteroaryl, substituted or unsubstituted bicyclic            heteroaryl, substituted or unsubstituted phenyl, or            substituted or unsubstituted naphthyl;    -   each R⁹ is independently selected from H, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,        substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        —C₁-C₄alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted aryl), and —C₁-C₄alkylene-(substituted or        unsubstituted heteroaryl); or    -   two R⁹ groups attached to the same N atom are taken together        with the N atom to which they are attached to form a substituted        or unsubstituted C₂-C₁₀heterocycloalkyl;    -   R¹⁰ is substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₁-C₆fluoroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted benzyl, a substituted or        unsubstituted heteroaryl, —C₁-C₄alkylene-(substituted or        unsubstituted C₃-C₁₀cycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted C₂-C₁₀heterocycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted aryl), or        —C₁-C₄alkylene-(substituted or unsubstituted heteroaryl);    -   R¹¹ is H or C₁-C₄alkyl.

For any and all of the embodiments, substituents are selected from amongfrom a subset of the listed alternatives. For example, in someembodiments, both R¹ are taken together with the carbon atom to whichthey are attached to form a substituted or unsubstitutedC₃-C₁₀cycloalkyl. In some embodiments, both R¹ are taken together withthe carbon atom to which they are attached to form a C₃-C₆cycloalkyl. Insome embodiments, both R¹ are taken together with the carbon atom towhich they are attached to form a substituted or unsubstitutedcyclopropyl, cyclobutyl, cyclopentyl, or cyclcohexyl. In someembodiments, both R¹ are taken together with the carbon atom to whichthey are attached to form a cyclopropyl. In some embodiments, both R¹are taken together with the carbon atom to which they are attached toform a cyclobutyl. In some embodiments, both R¹ are taken together withthe carbon atom to which they are attached to form a cyclopentyl. Insome embodiments, both R¹ are taken together with the carbon atom towhich they are attached to form a cyclohexyl. In some embodiments, eachR¹ is independently selected from H, —OH, C₁-C₆alkyl, andC₁-C₆fluoroalkyl. In some embodiments, each R¹ is independently selectedfrom H, —CH₃ and —CF₃. In some embodiments, each R¹ is —CH₃. In someembodiments, both R¹ are taken together with the carbon atom to whichthey are attached to form a cyclobutyl or each R¹ is —CH₃.

In some embodiments, both R² are taken together with the carbon to whichthey are attached to form —C(═S)— or —C(═O)—; both R³ are taken togetherwith the carbon to which they are attached to form —C(═O)—. In someembodiments, both R² are taken together with the carbon to which theyare attached to form —C(═S)—; both R³ are taken together with the carbonto which they are attached to form C(═O)—.

In some embodiments, ring A is C-linked monocyclic heteroaryl, C-linkedbicyclic heteroaryl, or naphthyl. In some embodiments, ring A isC-linked monocyclic heteroaryl. In some embodiments, ring A is C-linkedmonocyclic 5-membered or 6-membered heteroaryl. In some embodiments,ring A is C-linked monocyclic 6-membered heteroaryl. In someembodiments, ring A is an N-containing heteroaryl.

In some embodiments, both R¹ are taken together with the carbon atom towhich they are attached to form a substituted or unsubstitutedC₃-C₁₀cycloalkyl; both R² are taken together with the carbon to whichthey are attached to form —C(═S)—; both R³ are taken together with thecarbon to which they are attached to form —C(═O)—; ring A isN-containing monocyclic heteroaryl, or N-containing bicyclic heteroaryl;each R^(A) is independently selected from H, halogen, —CN, —NO₂, —OH,—S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰,—CO₂R⁹, —C(═O)N(R⁹)₂, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₁-C₆fluoroalkyl, substituted orunsubstituted C₁-C₆fluoroalkoxy, substituted or unsubstitutedC₁-C₆alkoxy, substituted or unsubstituted phenyl or substituted orunsubstituted monocyclic heteroaryl.

In some embodiments, both R¹ are taken together with the carbon atom towhich they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl,or cyclohexyl; ring A is N-containing monocyclic heteroaryl selectedfrom pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl,pyrazolyl, isothiazolyl, triazolyl, and tetrazolyl.

In some embodiments, ring A is pyridinyl, pyrimidinyl, pyridazinyl, orpyrazinyl. In some embodiments, ring A is pyridinyl.

In some embodiments,

In some embodiments,

In some embodiments, ring A is monosubstituted with R^(A). In someembodiments, ring A is disubstituted with R^(A). In some embodiments,ring A is trisubstituted with R^(A). In some embodiments, ring A issubstituted with —CN and at least one additional R^(A). In someembodiments, ring A is substituted with —CN and zero, one or twoadditional R^(A). In some embodiments, ring A is substituted with —CNand one or two additional R^(A). In some embodiments, ring A issubstituted with —CN and one additional R^(A).

In some embodiments, ring A is pyridinyl; each R^(A) is independentlyselected from H, halogen, —CN, —OH, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂,—C(═O)N(R⁹)₂, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆fluoroalkyl, substituted or unsubstitutedC₁-C₆fluoroalkoxy, substituted or unsubstituted C₁-C₆alkoxy, substitutedor unsubstituted phenyl or substituted or unsubstituted monocyclicheteroaryl.

In some embodiments, both R¹ are taken together with the carbon atom towhich they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl,or cyclohexyl; ring A is N-containing bicyclic heteroaryl selected fromquinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl,indolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl,benzothienyl, benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl,phthalazinyl, pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl,azaindolyl, pyrazolopyridinyl, thiazolopyrimidinyl, triazolopyridazinyl,thiazolopyridinyl, pyridothienyl, pyrimidiothienyl andpyrrolopyrimidinyl; each R^(A) is independently selected from H,halogen, —CN, —OH, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)N(R⁹)₂, substitutedor unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆fluoroalkoxy,substituted or unsubstituted C₁-C₆alkoxy, substituted or unsubstitutedphenyl or substituted or unsubstituted monocyclic heteroaryl.

In some embodiments, ring A is N-containing bicyclic heteroaryl selectedfrom quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,pyridopyrimidinyl, pyrazolopyrimidinyl, triazolopyridazinyl, andpyrrolopyrimidinyl.

In some embodiments, ring A is [1,2,4]triazolo[4,3-b]pyridazinyl.

In some embodiments, ring B is phenyl or monocyclic heteroaryl; each R⁴is independently selected from H, halogen, —CN, —NO₂, —OH, substitutedor unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆fluoroalkoxy,substituted or unsubstituted C₁-C₆alkoxy, and substituted orunsubstituted C₁-C₆heteroalkyl; R⁵ is substituted or unsubstitutedC₂-C₁₀alkyl, substituted or unsubstituted C₂-C₁₀fluoroalkyl, substitutedor unsubstituted C₂-C₁₀alkoxy, substituted or unsubstitutedC₂-C₁₀fluoroalkoxy, substituted or unsubstituted C₂-C₁₀heteroalkyl,substituted or unsubstituted C₂-C₁₀heterofluoroalkyl, or -L¹-L²-R⁶; R⁶;L¹ is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —C(═O)—, —C(═O)NH—,—NHC(═O)—, —NHS(═O)₂—, or —S(═O)₂NH—; L² is substituted or unsubstitutedC₁-C₆alkylene, substituted or unsubstituted C₁-C₆fluoroalkylene orsubstituted or unsubstituted C₁-C₆heteroalkylene; R⁶ is halogen, —CN,—NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,—CO₂R⁹, —N(R⁹)₂, —C(═O)N(R⁹)₂, substituted or unsubstitutedC₃-C₁₀cycloalkyl, substituted or unsubstituted C₂-C₁₀heterocycloalkyl,substituted or unsubstituted monocyclic heteroaryl, substituted orunsubstituted bicyclic heteroaryl, substituted or unsubstituted phenyl,or substituted or unsubstituted naphthyl.

In some embodiments, ring B is phenyl or monocyclic heteroaryl; each R⁴is independently selected from H, halogen, —CN, —NO₂, —OH, substitutedor unsubstituted C₁-C₄alkyl, substituted or unsubstitutedC₁-C₄fluoroalkyl, substituted or unsubstituted C₁-C₄fluoroalkoxy, andsubstituted or unsubstituted C₁-C₄alkoxy; R⁵ is substituted orunsubstituted C₂-C₁₀alkyl, substituted or unsubstitutedC₂-C₁₀fluoroalkyl, substituted or unsubstituted C₂-C₁₀alkoxy,substituted or unsubstituted C₂-C₁₀fluoroalkoxy, substituted orunsubstituted C₂-C₁₀heteroalkyl, substituted or unsubstitutedC₂-C₁₀heterofluoroalkyl, or -L¹-L²-R⁶; L¹ is absent, —O—, or —C(═O)NH—;L² is substituted or unsubstituted C₁-C₆alkylene, substituted orunsubstituted C₁-C₆fluoroalkylene or substituted or unsubstitutedC₁-C₆heteroalkylene; R⁶ is —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,—S(═O)₂R¹⁰, —C(═O)R¹⁰, —CO₂R⁹, —C(═O)N(R⁹)₂, substituted orunsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, substituted or unsubstituted monocyclicheteroaryl, substituted or unsubstituted bicyclic heteroaryl,substituted or unsubstituted phenyl, or substituted or unsubstitutednaphthyl.

In some embodiments, L² is substituted or unsubstituted C₁-C₆alkylene;R⁶ is —CN, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —C(═O)R¹⁰, —C(═O)N(R⁹)₂,substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted orunsubstituted C₂-C₁₀heterocycloalkyl, substituted or unsubstitutedmonocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl,substituted or unsubstituted phenyl, or substituted or unsubstitutednaphthyl.

In some embodiments, R⁶ is substituted or unsubstitutedC₃-C₁₀cycloalkyl, substituted or unsubstituted C₂-C₁₀heterocycloalkyl,substituted or unsubstituted monocyclic heteroaryl, substituted orunsubstituted bicyclic heteroaryl, substituted or unsubstituted phenyl,or substituted or unsubstituted naphthyl.

In some embodiments, L² is substituted or unsubstituted C₁-C₆alkylene;R⁶ is —CN, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —C(═O)R¹⁰, or—C(═O)N(R⁹)₂; each R⁹ is independently selected from H, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,—C₁-C₄alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),—C₁-C₄alkylene-(substituted or unsubstituted C₂-C₁₀heterocycloalkyl),—C₁-C₄alkylene-(substituted or unsubstituted aryl), and—C₁-C₄alkylene-(substituted or unsubstituted heteroaryl); or two R⁹groups attached to the same N atom are taken together with the N atom towhich they are attached to form a substituted or unsubstitutedC₂-C₁₀heterocycloalkyl; R¹⁰ is substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₁-C₆fluoroalkyl,—C₁-C₄alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),—C₁-C₄alkylene-(substituted or unsubstituted C₂-C₁₀heterocycloalkyl),—C₁-C₄alkylene-(substituted or unsubstituted aryl), or—C₁-C₄alkylene-(substituted or unsubstituted heteroaryl).

In some embodiments, provided is a compound of Formula (Ia), or apharmaceutically acceptable salt, or N-oxide thereof:

wherein,

-   -   ring A is monocyclic heteroaryl, bicyclic heteroaryl, or        naphthyl;    -   m is 1, 2, 3 or 4;    -   each R^(A) is independently H, halogen, —CN, —NO₂, —OH, —OR⁹,        —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂,        —C(═O)R¹⁰, —OC(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂, —C(═O)N(R⁹)₂,        C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, or        C₁-C₆heteroalkyl;    -   both R¹ are taken together with the carbon atom to which they        are attached to form a substituted or unsubstituted        C₃-C₆cycloalkyl or a substituted or unsubstituted        C₂-C₆heterocycloalkyl;    -   or each R¹ is independently selected from H, —OH, C₁-C₆alkyl,        C₁-C₆alkoxy, and C₁-C₆fluoroalkyl;    -   X is S or O;    -   ring B is phenyl, naphthyl, monocyclic heteroaryl, or bicyclic        heteroaryl;    -   n is 0, 1, 2, 3 or 4;    -   each R⁴ is independently selected from H, halogen, —CN, —NO₂,        —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰,        —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂,        —C(═O)N(R⁹)₂, —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰,        —NR¹¹C(═O)OR¹⁰, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy,        C₁-C₆alkoxy, and C₁-C₆heteroalkyl;    -   R⁵ is -L¹-L²-R⁶ or -L¹-R⁷;        -   L¹ is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —C(═O)—,            —C(═O)NH—, —NHC(═O)—, —NHC(═O)O—, —NHC(═O)NH—, —C(═O)O—,            —OC(═O)—, —OC(═O)O—, —OC(═O)NH—, —NHS(═O)₂—, or —S(═O)₂NH—;        -   L² is C₁-C₆alkylene, C₁-C₆fluoroalkylene or            C₁-C₆heteroalkylene;        -   R⁶ is halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,            —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,            —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂,            —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰,            —NR¹¹C(═O)OR¹⁰, C₁-C₆alkyl, C₁-C₆fluoroalkyl,            C₁-C₆heteroalkyl, substituted or unsubstituted            C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted            monocyclic heteroaryl, substituted or unsubstituted bicyclic            heteroaryl, substituted or unsubstituted phenyl, or            substituted or unsubstituted naphthyl;        -   R⁷ is substituted or unsubstituted monocyclic            C₂-C₆heterocycloalkyl, or substituted or unsubstituted            monocyclic heteroaryl;    -   each R⁹ is independently selected from H, C₁-C₆alkyl,        C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted phenyl,        substituted or unsubstituted monocyclic heteroaryl,        —C₁-C₄alkylene-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted monocyclic        C₂-C₆heterocycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted phenyl), and —C₁-C₄alkylene-(substituted or        unsubstituted monocyclic heteroaryl); or    -   two R⁹ groups attached to the same N atom are taken together        with the N atom to which they are attached to form a substituted        or unsubstituted monocyclic C₂-C₆heterocycloalkyl;    -   R¹⁰ is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, a        substituted or unsubstituted C₃-C₆cycloalkyl, a substituted or        unsubstituted monocyclic C₂-C₆heterocycloalkyl, a substituted or        unsubstituted phenyl, a substituted or unsubstituted benzyl, a        substituted or unsubstituted monocyclic heteroaryl,        —C₁-C₄alkylene-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted monocyclic        C₂-C₆heterocycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted phenyl), or —C₁-C₄alkylene-(substituted or        unsubstituted monocyclic heteroaryl);    -   R¹¹ is H or C₁-C₄alkyl.

In some embodiments, both R¹ are taken together with the carbon atom towhich they are attached to form a substituted or unsubstitutedC₃-C₆cycloalkyl; X is S; ring A is N-containing monocyclic heteroaryl;each R^(A) is independently selected from H, halogen, —CN, —NO², —OH,—S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰,—CO₂R⁹, —C(═O)N(R⁹)₂, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy,and C₁-C₆alkoxy; ring B is phenyl or monocyclic heteroaryl.

In some embodiments, both R¹ are taken together with the carbon atom towhich they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl,or cyclohexyl; ring A is pyridinyl, pyrimidinyl, pyridazinyl, orpyrazinyl.

In some embodiments, ring A is pyridinyl; each R^(A) is independentlyselected from H, halogen, —CN, —OH, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂,—C(═O)N(R⁹)₂, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, andC₁-C₆alkoxy.

In some embodiments, each R^(A) is independently selected from H,halogen, —CN, —OH, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)N(R⁹)₂, C₁-C₆alkyl,C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, and C₁-C₆alkoxy. In someembodiments, each R^(A) is independently selected from H, halogen, —CN,—OH, —C(═O)N(R⁹)₂, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄fluoroalkoxy, andC₁-C₄alkoxy. In some embodiments, each R^(A) is independently selectedfrom H, F, Cl, —CN, —OH, —C(═O)NH₂, —CH₃, —CH₂H₃, —CF₃, —OCF₃, —OCH₃,—CH₂CH₃.

In some embodiments, ring B is phenyl; R⁵ is -L¹-L²-R⁶; L¹ is absent,—O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —C(═O)—, —C(═O)NH—, —NHC(═O)—,—NHS(═O)₂—, or —S(═O)₂NH—; L² is C₁-C₆alkylene, C₁-C₆fluoroalkylene orC₁-C₆heteroalkylene; R⁶ is halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹,—S(═O)R¹⁰, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂,—C(═O)N(R⁹)₂, substituted or unsubstituted C₃-C₆cycloalkyl, substitutedor unsubstituted C₂-C₆heterocycloalkyl, substituted or unsubstitutedmonocyclic heteroaryl, or substituted or unsubstituted phenyl.

In some embodiments, ring B is phenyl; each R⁴ is independently selectedfrom H, halogen, —CN, —NO₂, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl,C₁-C₄fluoroalkoxy, and C₁-C₄alkoxy; R⁵ is -L¹-L²-R⁶; L¹ is absent, —O—,or —C(═O)NH—; L² is C₁-C₆alkylene, C₁-C₆fluoroalkylene orC₁-C₆heteroalkylene; R⁶ is —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,—S(═O)₂R¹⁰, —C(═O)R¹⁰, —CO₂R⁹, —C(═O)N(R⁹)₂, substituted orunsubstituted C₃-C₆cycloalkyl, substituted or unsubstitutedC₂-C₆heterocycloalkyl, substituted or unsubstituted monocyclicheteroaryl, or substituted or unsubstituted phenyl.

In some embodiments, L² is C₁-C₆alkylene; R⁶ is —CN, —OR⁹, —SR⁹,—S(═O)R¹⁰, —S(═O)₂R¹⁰, —C(═O)R¹⁰, —C(═O)N(R⁹)₂, substituted orunsubstituted C₃-C₆cycloalkyl, substituted or unsubstitutedC₂-C₆heterocycloalkyl, substituted or unsubstituted monocyclicheteroaryl, or substituted or unsubstituted phenyl.

In some embodiments, R⁶ is substituted or unsubstituted C₃-C₆cycloalkyl,substituted or unsubstituted C₂-C₆heterocycloalkyl, substituted orunsubstituted monocyclic heteroaryl, or substituted or unsubstitutedphenyl.

In some embodiments, if R⁶ is substituted, then R⁶ is substituted with 1or 2 groups independently selected from halogen, —CN, —NH₂, —NH(CH₃),—N(CH₃)₂, —OH, —CO₂H, —CO₂(C₁-C₄alkyl), —C(═O)C₁-C₄alkyl, —C(═O)NH₂,—C(═O)NH(C₁-C₄alkyl), —C(═O)N(C₁-C₄alkyl)₂, —S(═O)₂NH₂,—S(═O)₂NH(C₁-C₄alkyl), —S(═O)₂N(C₁-C₄alkyl)₂, C₁-C₄alkyl,C₃-C₆cycloalkyl, C₁-C₄fluoroalkyl, C₁-C₄heteroalkyl, C₁-C₄alkoxy,C₁-C₄fluoroalkoxy, —S—C₁-C₄alkyl, or —S(═O)₂C₁-C₄alkyl. In someembodiments, if R⁶ is substituted, then R⁶ is substituted with 1 or 2groups independently selected from halogen, —CN, —OH, —CO₂(C₁-C₄alkyl),—C(═O)C₁-C₄alkyl, —C(═O)NH₂, —C(═O)NH(C₁-C₄alkyl), —C(═O)N(C₁-C₄alkyl)₂,C₁-C₄alkyl, C₃-C₆cycloalkyl, C₄fluoroalkyl, C₁-C₄heteroalkyl,C₁-C₄alkoxy, and C₁-C₄fluoroalkoxy.

In some embodiments, L² is C₁-C₆alkylene; R⁶ is a substituted orunsubstituted C₂-C₆heterocycloalkyl. In some embodiments, L¹ is absent,—O—, or —C(═O)NH—; L² is C₁-C₆alkylene; R⁶ is a substituted orunsubstituted C₂-C₆heterocycloalkyl. In some embodiments, L¹ is—C(═O)NH—. In some embodiments, R⁶ is a substituted or unsubstitutedC₃-C₆heterocycloalkyl. In some embodiments, R⁶ is a substituted orunsubstituted N-containing C₂-C₆heterocycloalkyl.

In some embodiments, ring B is phenyl; each R⁴ is independently selectedfrom H, halogen, —CN, —NO₂, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl,C₁-C₄fluoroalkoxy, and C₁-C₄alkoxy; R⁵ is -L¹-R⁷; L¹ is absent, —O—,—S—, —S(═O)—, —S(═O)₂—, —NH—, —C(═O)—, —C(═O)NH—, —NHC(═O)—, —NHC(═O)O—,—NHC(═O)NH—, —C(═O)O—, —OC(═O)—, —OC(═O)O—, —OC(═O)NH—, —NHS(═O)₂—, or—S(═O)₂NH—; R⁷ is substituted or unsubstituted monocyclicC₂-C₆heterocycloalkyl, or substituted or unsubstituted monocyclicheteroaryl.

In some embodiments, L² is C₁-C₆alkylene. In some embodiments, L² isC₁-C₄alkylene. In some embodiments, L² is —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂—, or —CH₂CH₂CH₂CH₂CH₂CH₂—. In someembodiments, L² is —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, or —CH₂CH₂CH₂CH₂—.

In some embodiments, each R⁴ is independently selected from H, halogen,—OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄fluoroalkoxy, and C₁-C₄alkoxy.

In some embodiments, R⁵ is -L¹-R⁷.

In some embodiments, L¹ is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—,—C(═O)—, —C(═O)NH—, or —S(═O)₂NH—. In some embodiments, L¹ is absent. Insome embodiments, L¹ is —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —C(═O)—,—C(═O)NH—, or —S(═O)₂NH—. In some embodiments, L¹ is absent. In someembodiments, L¹ is —O—. In some embodiments, L¹ is absent. In someembodiments, L¹ is —C(═O)NH—.

In some embodiments, R⁵ is -L¹-R⁷; L¹ is —O—, —S—, —S(═O)—, —S(═O)₂—,—NH—, —C(═O)—, —C(═O)NH—, or —S(═O)₂NH—; R⁷ is substituted orunsubstituted monocyclic C₂-C₆heterocycloalkyl, or substituted orunsubstituted monocyclic heteroaryl.

In some embodiments, if R⁷ is substituted, then R⁷ is substituted with 1or 2 groups independently selected from halogen, —CN, —NH₂, —NH(CH₃),—N(CH₃)₂, —OH, —CO₂H, —CO₂(C₁-C₄alkyl), —C(═O)C₁-C₄alkyl, —C(═O)NH₂,—C(═O)NH(C₁-C₄alkyl), —C(═O)N(C₁-C₄alkyl)₂, —S(═O)₂NH₂,—S(═O)₂NH(C₁-C₄alkyl), —S(═O)₂N(C₁-C₄alkyl)₂, C₁-C₄alkyl,C₃-C₆cycloalkyl, C₁-C₄fluoroalkyl, C₁-C₄heteroalkyl, C₁-C₄alkoxy,C₁-C₄fluoroalkoxy, —S—C₁-C₄alkyl, or —S(═O)₂C₁-C₄alkyl. In someembodiments, if R⁷ is substituted, then R⁷ is substituted with 1 or 2groups independently selected from halogen, —CN, —OH, —CO₂(C₁-C₄alkyl),—C(═O)C₁-C₄alkyl, —C(═O)NH₂, —C(═O)NH(C₁-C₄alkyl), —C(═O)N(C₁-C₄alkyl)₂,C₁-C₄alkyl, C₃-C₆cycloalkyl, C₁-C₄fluoroalkyl, C₁-C₄heteroalkyl,C₁-C₄alkoxy, and C₁-C₄fluoroalkoxy.

In some embodiments, R⁵ is -L¹-R⁷; L¹ is absent, —O—, —S—, —S(═O)—,—S(═O)₂—, —NH—, —C(═O)—, —C(═O)NH—, or —S(═O)₂NH—; R⁷ is substituted orunsubstituted monocyclic heteroaryl.

In some embodiments, the compound of Formula (I) or Formula (Ia) has thestructure of Formula (II):

In some embodiments, the compound of Formula (Ia) has the structure ofFormula (II):

-   -   wherein,

-   -   m is 2;    -   one R^(A) is —CN, —NO₂, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,        —CO₂R⁹, or —C(═O)N(R⁹)₂; and the other R^(A) is H, halogen, —OH,        C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, or C₁-C₆alkoxy;    -   n is 0 or 1;    -   each R⁴ is independently selected from H, halogen, —CN, —NO₂,        —OH, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, and        C₁-C₆alkoxy;    -   R⁵ is -L¹-L²-R⁶ or -L¹-R⁷;        -   L¹ is absent, —O—, or —C(═O)NH—;        -   L² is C₁-C₆alkylene, C₁-C₆fluoroalkylene or            C₁-C₆heteroalkylene;        -   R⁶ is —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰,            —C(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂, —C(═O)N(R⁹)₂, substituted or            unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted            C₂-C₆heterocycloalkyl, substituted or unsubstituted            monocyclic heteroaryl, or substituted or unsubstituted            phenyl;        -   R⁷ is substituted or unsubstituted monocyclic            C₂-C₆heterocycloalkyl, or substituted or unsubstituted            monocyclic heteroaryl.

In some embodiments,

one R^(A) is —CN and the other R^(A) is H, halogen, —OH, C₁-C₄alkyl,C₁-C₄fluoroalkyl, C₁-C₄fluoroalkoxy, or C₁-C₄alkoxy; each R⁴ isindependently selected from H, halogen, —OH, C₁-C₄alkyl,C₁-C₄fluoroalkyl, C₁-C₄fluoroalkoxy, and C₁-C₄alkoxy; R⁵ is -L¹-L²-R⁶ or-L¹-R⁷; L¹ is absent, —O—, or —C(═O)NH—; L² is C₁-C₆alkylene,C₁-C₆fluoroalkylene or C₁-C₆heteroalkylene; R⁶ is —CN, —NO₂, —OH, —OR⁹,—SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —C(═O)R¹⁰, —CO₂R⁹, —C(═O)N(R⁹)₂,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₆heterocycloalkyl, substituted or unsubstitutedmonocyclic heteroaryl, or substituted or unsubstituted phenyl; R⁷ issubstituted or unsubstituted monocyclic C₂-C₆heterocycloalkyl, orsubstituted or unsubstituted monocyclic heteroaryl.

In some embodiments, described herein is a a compound of Formula (I), ora pharmaceutically acceptable salt, solvate, N-oxide, metabolite orprodrug thereof:

wherein,

-   -   ring A is bicyclic heteroaryl, or naphthyl;    -   m is 0, 1, 2, or 3;    -   each R^(A) is independently selected from H, halogen, —CN, —NO₂,        —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰,        —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂,        —C(═O)N(R⁹)₂, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆fluoroalkoxy, substituted or unsubstituted        C₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, substituted or        unsubstituted phenyl or substituted or unsubstituted monocyclic        heteroaryl;    -   each R¹ is independently selected from H, —OH, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆alkoxy, and substituted or unsubstituted C₁-C₆fluoroalkyl;    -   or both R¹ are taken together with the carbon atom to which they        are attached to form a substituted or unsubstituted        C₃-C₁₀cycloalkyl or a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl;    -   each R² is H; or both R² are taken together with the carbon to        which they are attached to form—C(═S)— or —C(═O)—;    -   each R³ is H; or both R³ are taken together with the carbon to        which they are attached to form—C(═S)— or —C(═O)—; provided that        each R² is not H if each R³ is H;    -   ring B is phenyl, naphthyl, monocyclic heteroaryl, or bicyclic        heteroaryl;    -   n is 0, 1, or 2;    -   each R⁴ is independently selected from H, halogen, —CN, —NO₂,        —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰,        —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂,        —C(═O)N(R⁹)₂, —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰,        —NR¹¹C(═O)OR¹⁰, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆fluoroalkoxy, substituted or unsubstituted        C₁-C₆alkoxy, and substituted or unsubstituted C₁-C₆heteroalkyl;    -   R⁵ is H, halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,        —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,        —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂,        —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰, —NR¹¹C(═O)OR¹⁰,        substituted or unsubstituted C₁-C₁₀alkyl, substituted or        unsubstituted C₁-C₁₀fluoroalkyl, substituted or unsubstituted        C₁-C₁₀fluoroalkoxy, C₁-C₁₀alkoxy, substituted or unsubstituted        C₁-C₁₀heteroalkyl, or -L¹-L²-R⁶;        -   L¹ is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —C(═O)—,            —C(═O)NH—, —NHC(═O)—, —NHC(═O)O—, —NHC(═O)NH—, —C(═O)O—,            —OC(═O)—, —OC(═O)O—, —OC(═O)NH—, —NHS(═O)₂—, or —S(═O)₂NH—;        -   L² is substituted or unsubstituted C₁-C₆alkylene,            substituted or unsubstituted C₁-C₆fluoroalkylene or            substituted or unsubstituted C₁-C₆heteroalkylene;        -   R⁶ is halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,            —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,            —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂,            —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰,            —NR¹¹C(═O)OR¹⁰, substituted or unsubstituted C₁-C₆alkyl,            substituted or unsubstituted C₁-C₆fluoroalkyl, substituted            or unsubstituted C₁-C₆heteroalkyl, substituted or            unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted            monocyclic heteroaryl, substituted or unsubstituted bicyclic            heteroaryl, substituted or unsubstituted phenyl, or            substituted or unsubstituted naphthyl;    -   each R⁹ is independently selected from H, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,        a substituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted        or unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or        unsubstituted aryl, a substituted or unsubstituted heteroaryl,        —C₁-C₄alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted aryl), and —C₁-C₄alkylene-(substituted or        unsubstituted heteroaryl); or    -   two R⁹ groups attached to the same N atom are taken together        with the N atom to which they are attached to form a substituted        or unsubstituted C₂-C₁₀heterocycloalkyl;    -   R¹⁰ is substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₁-C₆fluoroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₄alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted aryl), or —C₁-C₄alkylene-(substituted or        unsubstituted heteroaryl);    -   R¹¹ is H or C₁-C₄alkyl.

In some embodiments, ring A is selected from quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl, indazolyl,benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothienyl,benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl, phthalazinyl,pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, azaindolyl,pyrazolopyridinyl, thiazolopyrimidinyl, triazolopyridazinyl,thiazolopyridinyl, pyridothienyl, pyrimidiothienyl, pyrrolopyrimidinyland naphthyl.

In some embodiments, ring A is selected from quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, pyridopyrimidinyl, pyrazolopyrimidinyl,triazolopyridazinyl, pyrrolopyrimidinyl, and napthyl.

In some embodiments, ring A is [1,2,4]triazolo[4,3-b]pyridazinyl.

In some embodiments, described herein is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, N-oxide, metabolite orprodrug thereof:

wherein,

-   -   ring A is a 5-membered heteroaryl;    -   m is 0, 1, 2, or 3;    -   each R^(A) is independently selected from H, halogen, —CN, —NO₂,        —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰,        —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂,        —C(═O)N(R⁹)₂, substituted or unsubstituted C₁-C₄alkyl,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆fluoroalkoxy, substituted or unsubstituted        C₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, substituted or        unsubstituted phenyl or substituted or unsubstituted monocyclic        heteroaryl;    -   each R¹ is independently selected from H, —OH, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆alkoxy, and substituted or unsubstituted C₁-C₆fluoroalkyl;    -   or both R¹ are taken together with the carbon atom to which they        are attached to form a substituted or unsubstituted        C₃-C₁₀cycloalkyl or a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl;    -   each R² is H; or both R² are taken together with the carbon to        which they are attached to form—C(═S)— or —C(═O)—;    -   each R³ is H; or both R³ are taken together with the carbon to        which they are attached to form—C(═S)— or —C(═O)—; provided that        each R² is not H if each R³ is H; ring B is phenyl, naphthyl,        monocyclic heteroaryl, or bicyclic heteroaryl;    -   n is 0, 1, or 2;    -   each R⁴ is independently selected from H, halogen, —CN, —NO₂,        —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰,        —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂,        —C(═O)N(R⁹)₂, —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰,        —NR¹¹C(═O)OR¹⁰, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆fluoroalkoxy, substituted or unsubstituted        C₁-C₆alkoxy, and substituted or unsubstituted C₁-C₆heteroalkyl;    -   R⁵ is H, halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,        —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,        —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂,        —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰, —NR¹¹C(═O)OR¹⁰,        substituted or unsubstituted C₁-C₁₀alkyl, substituted or        unsubstituted C₁-C₁₀fluoroalkyl, substituted or unsubstituted        C₁-C₁₀fluoroalkoxy, substituted or unsubstituted C₁-C₁₀alkoxy,        substituted or unsubstituted C₁-C₁₀heteroalkyl, or -L¹-L²-R⁶;        -   L¹ is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —C(═O)—,            —C(═O)NH—, —NHC(═O)—, —NHC(═O)O—, —NHC(═O)NH—, —C(═O)O—,            —OC(═O)—, —OC(═O)O—, —OC(═O)NH—, —NHS(═O)₂—, or —S(═O)₂NH—;        -   L² is substituted or unsubstituted C₁-C₆alkylene,            substituted or unsubstituted C₁-C₆fluoroalkylene or            substituted or unsubstituted C₁-C₆heteroalkylene;        -   R⁶ is halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,            —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,            —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂,            —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰,            —NR¹¹C(═O)OR¹⁰, substituted or unsubstituted C₁-C₆alkyl,            substituted or unsubstituted C₁-C₆fluoroalkyl, substituted            or unsubstituted C₁-C₆heteroalkyl, substituted or            unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted            monocyclic heteroaryl, substituted or unsubstituted bicyclic            heteroaryl, substituted or unsubstituted phenyl, or            substituted or unsubstituted naphthyl;    -   each R⁹ is independently selected from H, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,        a substituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted        or unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or        unsubstituted aryl, a substituted or unsubstituted heteroaryl,        —C₁-C₄alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted aryl), and —C₁-C₄alkylene-(substituted or        unsubstituted heteroaryl); or    -   two R⁹ groups attached to the same N atom are taken together        with the N atom to which they are attached to form a substituted        or unsubstituted C₂-C₁₀heterocycloalkyl;    -   R¹⁰ is substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₁-C₆fluoroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₄alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted aryl), or —C₁-C₄alkylene-(substituted or        unsubstituted heteroaryl);    -   R¹¹ is H or C₁-C₄alkyl.

In some embodiments, ring A is selected from pyrrolyl, thiazolyl,oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, isothiazolyl,triazolyl, and tetrazolyl.

In some embodiments,

is selected from:

where X is O, S, or NR^(A). In some embodiments, X is O. In someembodiments, X is S. In some embodiments, X is NR^(A).

In some embodiments, both R¹ are taken together with the carbon atom towhich they are attached to form a C₃-C₁₀cycloalkyl; both R² are takentogether with the carbon to which they are attached to form —C(═S)—;both R³ are taken together with the carbon to which they are attached toform —C(═O)—.

In some embodiments, the compound described herein has the structure ofFormula (III):

-   -   wherein,    -   p is 0, 1, 2, or 3.

In some embodiments, each R^(A) is independently selected from H,halogen, —CN, —NO₂, —OH, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —CO₂R⁹,—C(═O)N(R⁹)₂, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆fluoroalkyl, substituted or unsubstitutedC₁-C₆fluoroalkoxy, substituted or unsubstituted C₁-C₆alkoxy, substitutedor unsubstituted phenyl or substituted or unsubstituted monocyclicheteroaryl.

In some embodiments, each R⁴ is independently selected from H, halogen,—CN, —NO₂, —OH, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆fluoroalkyl, substituted or unsubstitutedC₁-C₆fluoroalkoxy, and substituted or unsubstituted C₁-C₆alkoxy; R⁵ issubstituted or unsubstituted C₂-C₁₀alkyl, substituted or unsubstitutedC₂-C₁₀fluoroalkyl, substituted or unsubstituted C₂-C₁₀alkoxy,substituted or unsubstituted C₂-C₁₀fluoroalkoxy, substituted orunsubstituted C₂-C₁₀heteroalkyl, substituted or unsubstitutedC₂-C₁₀heterofluoroalkyl, or -L¹-L²-R⁶; L¹ is absent, —O—, —S—, —S(═O)—,—S(═O)₂—, —NH—, —C(═O)—, —C(═O)NH—, —NHC(═O)—, —NHS(═O)₂—, or—S(═O)₂NH—; L² is substituted or unsubstituted C₁-C₆alkylene,substituted or unsubstituted C₁-C₆fluoroalkylene or substituted orunsubstituted C₁-C₆heteroalkylene; R⁶ is halogen, —CN, —NO₂, —OH, —OR⁹,—SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂,—C(═O)N(R⁹)₂, substituted or unsubstituted C₃-C₁₀cycloalkyl, substitutedor unsubstituted C₂-C₁₀heterocycloalkyl, substituted or unsubstitutedmonocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl,substituted or unsubstituted phenyl, or substituted or unsubstitutednaphthyl.

In some embodiments, each R⁴ is independently selected from H, halogen,—CN, —NO₂, —OH, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆fluoroalkyl, substituted or unsubstitutedC₁-C₆fluoroalkoxy, and substituted or unsubstituted C₁-C₆alkoxy; R⁵ isH, halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰,—S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —CO₂R⁹, —C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰,—NR¹¹C(═O)OR¹⁰, substituted or unsubstituted C₁-C₁₀alkyl, substituted orunsubstituted C₁-C₁₀fluoroalkyl, substituted or unsubstitutedC₁-C₁₀fluoroalkoxy, substituted or unsubstituted C₁-C₁₀alkoxy,substituted or unsubstituted C₁-C₁₀heteroalkyl, or -L¹-L²-R⁶; L¹ isabsent, —O—, or —C(═O)NH—; L² is C₁-C₆alkylene, C₁-C₆fluoroalkylene orC₁-C₆heteroalkylene; R⁶ is —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,—S(═O)₂R¹⁰, —C(═O)R¹⁰, —CO₂R⁹, —C(═O)N(R⁹)₂, substituted orunsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, substituted or unsubstituted monocyclicheteroaryl, substituted or unsubstituted bicyclic heteroaryl,substituted or unsubstituted phenyl, or substituted or unsubstitutednaphthyl.

In some embodiments, the compound described herein has the structure ofFormula (III):

wherein,

-   -   ring A is monocyclic heteroaryl, bicyclic heteroaryl, or        naphthyl;    -   m is 1 or 2;    -   each R^(A) is independently H, halogen, —CN, —NO₂, —OH, —OR⁹,        —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂,        —C(═O)R¹⁰, —OC(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂, —C(═O)N(R⁹)₂,        C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, or        C₁-C₆heteroalkyl;    -   ring B is phenyl, naphthyl, monocyclic heteroaryl, or bicyclic        heteroaryl;    -   n is 0, 1 or 2;    -   each R⁴ is independently selected from H, halogen, —CN, —NO₂,        —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰,        —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂,        —C(═O)N(R⁹)₂, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy,        C₁-C₆alkoxy, and C₁-C₆heteroalkyl;    -   R⁵ is substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted        or unsubstituted C₂-C₁₀heterocycloalkyl, substituted or        unsubstituted phenyl, substituted or unsubstituted monocyclic        heteroaryl, -L¹-L²-R⁶ or -L¹-R⁷;        -   L¹ is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —C(═O)—,            —C(═O)NH—, —NHC(═O)—, —NHC(═O)O—, —NHC(═O)NH—, —C(═O)O—,            —OC(═O)—, —OC(═O)O—, —OC(═O)NH—, —NHS(═O)₂—, or —S(═O)₂NH—;        -   L² is C₁-C₆alkylene, C₁-C₆fluoroalkylene or            C₁-C₆heteroalkylene;        -   R⁶ is halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,            —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,            —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂,            —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰,            —NR¹¹C(═O)OR¹⁰, C₁-C₆alkyl, C₁-C₆fluoroalkyl,            C₁-C₆heteroalkyl, substituted or unsubstituted            C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted            monocyclic heteroaryl, substituted or unsubstituted bicyclic            heteroaryl, substituted or unsubstituted phenyl, or            substituted or unsubstituted naphthyl;        -   R⁷ is substituted or unsubstituted C₃-C₁₀cycloalkyl,            substituted or unsubstituted monocyclic            C₂-C₆heterocycloalkyl, substituted or unsubstituted            monocyclic phenyl, or substituted or unsubstituted            monocyclic heteroaryl;        -   each R⁹ is independently selected from H, C₁-C₆alkyl,            C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, a substituted or            unsubstituted C₃-C₁₀cycloalkyl, a substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or            unsubstituted aryl, a substituted or unsubstituted benzyl, a            substituted or unsubstituted heteroaryl,            —C₁-C₄alkylene-(substituted or unsubstituted            C₃-C₁₀cycloalkyl), —C₁-C₄alkylene-(substituted or            unsubstituted C₂-C₁₀heterocycloalkyl),            —C₁-C₄alkylene-(substituted or unsubstituted aryl), and            —C₁-C₄alkylene-(substituted or unsubstituted heteroaryl); or        -   two R⁹ groups attached to the same N atom are taken together            with the N atom to which they are attached to form a            substituted or unsubstituted C₂-C₁₀heterocycloalkyl;        -   R¹⁰ is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, a            substituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted            or unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or            unsubstituted aryl, a substituted or unsubstituted benzyl, a            substituted or unsubstituted heteroaryl,            —C₁-C₄alkylene-(substituted or unsubstituted            C₃-C₁₀cycloalkyl), —C₁-C₄alkylene-(substituted or            unsubstituted C₂-Cioheterocycloalkyl),            —C₁-C₄alkylene-(substituted or unsubstituted aryl), or            —C₁-C₄alkylene-(substituted or unsubstituted heteroaryl);        -   R¹¹ is H or C₁-C₄alkyl;        -   p is 0, 1, 2, or 3.

In some embodiments, R⁵ is C₃-C₆cycloalkyl, substituted or unsubstitutedC₂-C₆heterocycloalkyl, substituted or unsubstituted phenyl, substitutedor unsubstituted monocyclic 5-membered or 6-membered heteroaryl,-L¹-L²-R⁶ or -L¹-R⁷; L¹ is absent, —O—, or —C(═O)NH—; L² isC₁-C₆alkylene; R⁶ is C₃-C₆cycloalkyl, substituted or unsubstitutedC₂-C₆heterocycloalkyl, substituted or unsubstituted monocyclic5-membered or 6-membered heteroaryl, or substituted or unsubstitutedphenyl; R⁷ is C₃-C₆cycloalkyl, substituted or unsubstituted monocyclicC₂-C₆heterocycloalkyl, substituted or unsubstituted monocyclic phenyl,or substituted or unsubstituted monocyclic 5-membered or 6-memberedheteroaryl.

In some embodiments, described herein is a compound of Formula (IV), ora pharmaceutically acceptable salt, solvate, N-oxide, metabolite orprodrug thereof:

wherein,

-   -   each R¹ is independently selected from H, —OH, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆alkoxy, and substituted or unsubstituted C₁-C₆fluoroalkyl;    -   or both R¹ are taken together with the carbon atom to which they        are attached to form a substituted or unsubstituted        C₃-C₁₀cycloalkyl or a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl;        -   X¹ is CR^(A) or N;        -   X² is CR^(A) or N;        -   X³ is CR^(A) or N; provided that at least two of X¹, X², and            X³ is CR^(A);        -   each R^(A) is independently selected from H, halogen, —CN,            —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰,            —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰,            —CO₂R⁹, —N(R⁹)₂, —C(═O)N(R⁹)₂, substituted or unsubstituted            C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,            substituted or unsubstituted C₁-C₆fluoroalkoxy, substituted            or unsubstituted C₁-C₆alkoxy, substituted or unsubstituted            C₁-C₆heteroalkyl, substituted or unsubstituted            C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted phenyl            or substituted or unsubstituted monocyclic heteroaryl;        -   ring B is phenyl, naphthyl, monocyclic heteroaryl, or            bicyclic heteroaryl;        -   n is 0, 1, or 2;        -   R⁴ is H, halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,            —S(═O)₂R¹⁰, substituted or unsubstituted C₁-C₆alkyl,            substituted or unsubstituted C₁-C₆fluoroalkyl, substituted            or unsubstituted C₁-C₆fluoroalkoxy, substituted or            unsubstituted C₁-C₆alkoxy, or substituted or unsubstituted            C₁-C₆heteroalkyl;        -   R⁵ is halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,            —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,            —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —OC(═O)N(R⁹)₂,            —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰, —NR¹¹C(═O)OR¹⁰, substituted            or unsubstituted C₂-C₁₀alkyl, substituted or unsubstituted            C₂-C₁₀fluoroalkyl, substituted or unsubstituted            C₁-C₁₀fluoroalkoxy, substituted or unsubstituted C₁₀alkoxy,            substituted or unsubstituted C₁-C₁₀heteroalkyl, substituted            or unsubstituted C₃-C₁₀cycloalkyl, substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, substituted or            unsubstituted phenyl, substituted or unsubstituted            monocyclic heteroaryl, or -L¹-L²-R⁶;            -   L¹ is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NH—, —C(═O)—,                —C(═O)NH—, —NHC(═O)—, —NHC(═O)O—, —NHC(═O)NH—, —C(═O)O—,                —OC(═O)—, —OC(═O)O—, —OC(═O)NH—, —NHS(═O)₂—, or                —S(═O)₂NH—;            -   L² is substituted or unsubstituted C₁-C₆alkylene,                substituted or unsubstituted C₁-C₆fluoroalkylene or                substituted or unsubstituted C₁-C₆heteroalkylene;            -   R⁶ is —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰,                —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰,                —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂, —OC(═O)N(R⁹)₂,                —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰, —NR¹¹C(═O)OR¹⁰,                substituted or unsubstituted C₃-C₁₀cycloalkyl,                substituted or unsubstituted C₂-C₁₀heterocycloalkyl,                substituted or unsubstituted monocyclic heteroaryl,                substituted or unsubstituted bicyclic heteroaryl, or                substituted or unsubstituted aryl;        -   each R⁹ is independently selected from H, substituted or            unsubstituted substituted or unsubstituted C₁-C₆heteroalkyl,            substituted or unsubstituted C₁-C₆fluoroalkyl, a substituted            or unsubstituted C₃-C₁₀cycloalkyl, a substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or            unsubstituted aryl, a substituted or unsubstituted benzyl, a            substituted or unsubstituted heteroaryl,            —C₁-C₄alkylene-(substituted or unsubstituted            C₃-C₁₀cycloalkyl), —C₁-C₄alkylene-(substituted or            unsubstituted C₂-C₁₀heterocycloalkyl),            —C₁-C₄alkylene-(substituted or unsubstituted aryl), and            —C₁-C₄alkylene-(substituted or unsubstituted heteroaryl); or        -   two R⁹ groups attached to the same N atom are taken together            with the N atom to which they are attached to form a            substituted or unsubstituted C₂-C₁₀heterocycloalkyl;        -   R¹⁰ is substituted or unsubstituted C₁-C₆alkyl, substituted            or unsubstituted C₁-C₆heteroalkyl, substituted or            unsubstituted C₁-C₆fluoroalkyl, a substituted or            unsubstituted C₃-C₁₀cycloalkyl, a substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or            unsubstituted aryl, a substituted or unsubstituted benzyl, a            substituted or unsubstituted heteroaryl,            —C₁-C₄alkylene-(substituted or unsubstituted            C₃-C₁₀cycloalkyl), —C₁-C₄alkylene-(substituted or            unsubstituted C₂-C₁₀heterocycloalkyl),            —C₁-C₄alkylene-(substituted or unsubstituted aryl), or            —C₁-C₄alkylene-(substituted or unsubstituted heteroaryl);        -   R¹¹ is H or C₁-C₄alkyl.

In some embodiments,

where X¹ is CR^(A) or N; X² is CR^(A) or N; X³ is CR^(A) or N; providedthat at least two of X¹, X², and X³ is CR^(A).

In some embodiments,

m is 0, 1, 2, 3, or 4.

In some embodiments,

In some embodiments, the compound of Formula (IV) has the structure ofFormula (V):

In some embodiments, ring B is phenyl; R⁴ is H, halogen, —CN, —OH,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆fluoroalkoxy, orsubstituted or unsubstituted C₁-C₆alkoxy; R⁵ is halogen, —CN, —NO₂, —OH,—OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —CO₂R⁹,—N(R⁹)₂, substituted or unsubstituted C₂-C₁₀alkyl, substituted orunsubstituted C₂-C₁₀fluoroalkyl, substituted or unsubstitutedC₁-C₁₀fluoroalkoxy, substituted or unsubstituted C₁-C₁₀alkoxy,substituted or unsubstituted C₁-C₁₀heteroalkyl, substituted orunsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, substituted or unsubstituted phenyl, substitutedor unsubstituted monocyclic heteroaryl, or -L¹-L²-R⁶; L¹ is absent, —O—,—S—, —S(O)—, —S(O)₂—, —NH—, —C(═O)—, —C(═O)NH—, or —S(═O)₂NH—; L² issubstituted or unsubstituted C₆alkylene, substituted or unsubstitutedC₁-C₆fluoroalkylene or substituted or unsubstituted C₆heteroalkylene; R⁶is —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂,—CO₂R⁹, —C(═O)N(R⁹)₂, substituted or unsubstituted C₃-C₁₀cycloalkyl,substituted or unsubstituted C₂-C₁₀heterocycloalkyl, substituted orunsubstituted monocyclic heteroaryl, substituted or unsubstitutedbicyclic heteroaryl, or substituted or unsubstituted aryl.

In some embodiments, each R^(A) is independently selected from H,halogen, —CN, —NO₂, —OH, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —CO₂R⁹,—C(═O)N(R⁹)₂, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆fluoroalkyl, substituted or unsubstitutedC₁-C₆fluoroalkoxy, or substituted or unsubstituted C₁-C₆alkoxy.

In some embodiments, the compound of Formula (I), (Ia), (II), (IV) or(V) has the structure of Formula (VI):

In some embodiments, the compound of Formula (I), (Ia), (II), (IV) or(V) has the structure of Formula (VI):

-   -   wherein,    -   one R^(A) is —CN, —NO₂, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,        —CO₂R⁹, or —C(═O)N(R⁹)₂; and the other R^(A) is H, halogen, —OH,        C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, or C₁-C₆alkoxy;    -   both R¹ are taken together with the carbon atom to which they        are attached to form a C₃-C₆cycloalkyl;    -   or each R¹ is independently C₁-C₄alkyl;    -   R⁴ is H, halogen, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl,        C₁-C₄fluoroalkoxy, or C₁-C₄alkoxy.

In some embodiments, R⁵ is -L¹-L²-R⁶ or -L¹-R⁷; L¹ is absent, —O—, or—C(═O)NH—; L² is C₁-C₆alkylene, C₁-C₆fluoroalkylene orC₁-C₆heteroalkylene; R⁶ is —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,—S(═O)₂R¹⁰, —C(═O)R¹⁰, —CO₂R⁹, —C(═O)N(R⁹)₂, substituted orunsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted monocyclicC₂-C₆heterocycloalkyl, substituted or unsubstituted monocyclicheteroaryl, or substituted or unsubstituted phenyl; R⁷ is substituted orunsubstituted monocyclic C₂-C₆heterocycloalkyl, or substituted orunsubstituted monocyclic heteroaryl.

In some embodiments, one R^(A) is —CN; and the other R^(A) is H, F, C1,—OH, —CH₃, —CF₃, —OCF₃, —OCH₃ or —OCH₂CH₃. In some embodiments, oneR^(A) is —CN; and the other R^(A) is —CH₃, or —CF₃.

In some embodiments, both R¹ are taken together with the carbon atom towhich they are attached to form a cyclobutyl; or each R¹ is —CH₃.

In some embodiments, R⁵ is -L¹-L²-R⁶ or -L¹-R⁷; L¹ is absent, —O—, or—C(═O)NH—; L² is C₁-C₆alkylene; R⁶ is substituted or unsubstitutedC₃-C₆cycloalkyl, substituted or unsubstituted monocyclicC₂-C₆heterocycloalkyl, substituted or unsubstituted monocyclicheteroaryl, or substituted or unsubstituted phenyl; R⁷ is substituted orunsubstituted monocyclic C₂-C₆heterocycloalkyl, or substituted orunsubstituted monocyclic heteroaryl. In some embodiments, R⁵ is-L¹-L²-R⁶; L¹ is —C(═O)NH—; L² is C₁-C₄alkylene; substituted orunsubstituted N-containing 5-membered or 6-memberedC₂-C₆heterocycloalkyl. In some embodiments, R⁵ is -L¹-R⁷; L¹ is absent,—O—, or —C(═O)NH—; R⁷ is substituted or unsubstituted monocyclic5-membered or 6-membered C₂-C₆heterocycloalkyl, or substituted orunsubstituted monocyclic 5-membered or 6-membered heteroaryl.

In some embodiments, one R^(A) is —CN, —NO₂, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂,—C(═O)R¹⁰, —CO₂R⁹, —C(═O)N(R⁹)₂, substituted or unsubstituted phenyl orsubstituted or unsubstituted monocyclic heteroaryl; and the other R^(A)is H, halogen, —OH, substituted or unsubstituted C₁-C₆alkyl, substitutedor unsubstituted C₁-C₆fluoroalkyl, substituted or unsubstitutedC₁-C₆fluoroalkoxy, or substituted or unsubstituted C₁-C₆alkoxy; R⁴ is H,halogen, —CN, —OH, substituted or unsubstituted C₁-C₆alkyl, substitutedor unsubstituted C₁-C₆fluoroalkyl, substituted or unsubstitutedC₁-C₆fluoroalkoxy, or substituted or unsubstituted C₁-C₆alkoxy; R⁵ ishalogen, —CN, —NO₂, —OH, —OR⁹, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,—CO₂R⁹, substituted or unsubstituted C₂-C₁₀alkyl, substituted orunsubstituted C₂-C₁₀fluoroalkyl, substituted or unsubstitutedC₁-C₁₀fluoroalkoxy, substituted or unsubstituted C₁-C₁₀alkoxy,substituted or unsubstituted C₁-C₁₀heteroalkyl, substituted orunsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, substituted or unsubstituted phenyl, substitutedor unsubstituted monocyclic heteroaryl, or -L¹-L²-R⁶; L¹ is absent, —O—,or —C(═O)NH—; L² is substituted or unsubstituted C₁-C₆alkylene,substituted or unsubstituted C₁-C₆fluoroalkylene or substituted orunsubstituted C₁-C₆heteroalkylene; R⁶ is —CN, —NO₂, —OH, —OR⁹, —SR⁹,—S(═O)R¹⁰, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —CO₂R⁹, —C(═O)N(R⁹)₂, substitutedor unsubstituted monocyclic heteroaryl, or substituted or unsubstitutedphenyl.

In some embodiments, described herein is a compound of Formula (VII), ora pharmaceutically acceptable salt, solvate, N-oxide, metabolite orprodrug thereof:

-   -   wherein,    -   each R¹ is independently selected from H, —OH, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆alkoxy, and substituted or unsubstituted C₁-C₆fluoroalkyl;    -   or both R¹ are taken together with the carbon atom to which they        are attached to form a substituted or unsubstituted        C₃-C₁₀cycloalkyl or a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl;    -   each R^(A) is independently selected from H, halogen, —CN, —NO₂,        —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰,        —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂,        —C(═O)N(R⁹)₂, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆fluoroalkoxy, substituted or unsubstituted        C₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        phenyl or substituted or unsubstituted monocyclic heteroaryl;    -   ring B is 5-membered heteroaryl, bicyclic heteroaryl or        naphthyl;    -   n is 0, 1, or 2;    -   R⁴ is H, halogen, —CN, —NO₂, —OH, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,        substituted or unsubstituted C₁-C₆fluoroalkoxy, or substituted        or unsubstituted C₁-C₆alkoxy;    -   R⁵ is H, halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,        —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,        —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂,        —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰, —NR¹¹C(═O)OR¹⁰,        substituted or unsubstituted C₂-C₁₀alkyl, substituted or        unsubstituted C₂-C₁₀fluoroalkyl, substituted or unsubstituted        C₁-C₁₀fluoroalkoxy, substituted or unsubstituted C₁-C₁₀alkoxy,        substituted or unsubstituted C₁-C₁₀heteroalkyl, substituted or        unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted phenyl,        substituted or unsubstituted monocyclic heteroaryl, or        -L¹-L²-R⁶;        -   L¹ is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NH—, —C(═O)—,            —C(═O)NH—, —NHC(═O)—, —NHC(═O)O—, —NHC(═O)NH—, —C(═O)O—,            —OC(═O)—, —OC(═O)O—, —OC(═O)NH—, —NHS(═O)₂—, or —S(═O)₂NH—;        -   L² is substituted or unsubstituted C₁-C₆alkylene,            substituted or unsubstituted C₁-C₆fluoroalkylene or            substituted or unsubstituted C₁-C₆heteroalkylene;        -   R⁶ is halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,            —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,            —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂,            —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰,            —NR¹¹C(═O)OR¹⁰, substituted or unsubstituted            C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted            monocyclic heteroaryl, substituted or unsubstituted bicyclic            heteroaryl, or substituted or unsubstituted aryl;    -   each R⁹ is independently selected from H, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,        a substituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted        or unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or        unsubstituted aryl, a substituted or unsubstituted benzyl, a        substituted or unsubstituted heteroaryl,        —C₁-C₄alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted aryl), and —C₁-C₄alkylene-(substituted or        unsubstituted heteroaryl); or    -   two R⁹ groups attached to the same N atom are taken together        with the N atom to which they are attached to form a substituted        or unsubstituted C₂-C₁₀heterocycloalkyl;    -   R¹⁰ is substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted        C₁-C₆fluoroalkyl, a substituted or unsubstituted        C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted benzyl, a substituted or        unsubstituted heteroaryl, —C₁-C₄alkylene-(substituted or        unsubstituted C₃-C₁₀cycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted C₂-C₁₀heterocycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted aryl), or        —C₁-C₄alkylene-(substituted or unsubstituted heteroaryl);    -   R¹¹ is H or C₁-C₄alkyl.

In some embodiments, described herein is a compound of Formula (VIII),or a pharmaceutically acceptable salt, solvate, N-oxide, metabolite orprodrug thereof:

wherein,

-   -   each R¹ is independently selected from H, —OH, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆alkoxy, and substituted or unsubstituted C₁-C₆fluoroalkyl;    -   or both R¹ are taken together with the carbon atom to which they        are attached to form a substituted or unsubstituted        C₃-C₆cycloalkyl or a substituted or unsubstituted        C₂-C₆heterocycloalkyl;    -   X is O or S;    -   each R^(A) is independently selected from H, halogen, —CN, —NO₂,        —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰,        —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂,        —C(═O)N(R⁹)₂, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, substituted or        unsubstituted phenyl or substituted or unsubstituted monocyclic        heteroaryl;        -   ring B is phenyl, naphthyl, monocyclic heteroaryl, or            bicyclic heteroaryl;        -   n is 0, 1, or 2;        -   R⁴ is H, halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,            —S(═O)₂R¹⁰, substituted or unsubstituted C₁-C₆alkyl,            substituted or unsubstituted C₁-C₆fluoroalkyl, substituted            or unsubstituted C₁-C₆fluoroalkoxy, substituted or            unsubstituted C₁-C₆alkoxy, or substituted or unsubstituted            C₁-C₆heteroalkyl;        -   R⁵ is halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,            —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,            —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂,            —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰,            —NR¹¹C(═O)OR¹⁰, substituted or unsubstituted C₁-C₁₀alkyl,            substituted or unsubstituted C₁-C₁₀fluoroalkyl, substituted            or unsubstituted C₁-C₁₀fluoroalkoxy, substituted or            unsubstituted C₁-C₁₀alkoxy, substituted or unsubstituted            C₁-C₁₀heteroalkyl, substituted or unsubstituted            C₃-C₁₀cycloalkyl, substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, substituted or unsubstituted phenyl,            substituted or unsubstituted monocyclic heteroaryl, or            -L¹-L²-R⁶;            -   L¹ is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NH—, —C(═O)—,                —C(═O)NH—, —NHC(═O)—, —NHC(═O)O—, —NHC(═O)NH—, —C(═O)O—,                —OC(═O)—, —OC(═O)O—, —OC(═O)NH—, —NHS(═O)₂—, or                —S(═O)₂NH—;            -   L² is substituted or unsubstituted C₁-C₆alkylene,                substituted or unsubstituted C₁-C₆fluoroalkylene or                substituted or unsubstituted C₁-C₆heteroalkylene;            -   R⁶ is —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰,                —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰,                —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂, —OC(═O)N(R⁹)₂,                —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰, —NR¹¹C(═O)OR¹⁰,                substituted or unsubstituted C₃-C₁₀cycloalkyl,                substituted or unsubstituted C₂-C₁₀heterocycloalkyl,                substituted or unsubstituted monocyclic heteroaryl,                substituted or unsubstituted bicyclic heteroaryl, or                substituted or unsubstituted aryl;        -   each R⁹ is independently selected from H, substituted or            unsubstituted C₁-C₆alkyl, substituted or unsubstituted            C₁-C₆heteroalkyl, substituted or unsubstituted            C₁-C₆fluoroalkyl, a substituted or unsubstituted            C₃-C₁₀cycloalkyl, a substituted or unsubstituted            C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl,            a substituted or unsubstituted benzyl, a substituted or            unsubstituted heteroaryl, —C₁-C₄alkylene-(substituted or            unsubstituted C₃-C₁₀cycloalkyl), —C₁-C₄alkylene-(substituted            or unsubstituted C₂-C₁₀heterocycloalkyl),            —C₁-C₄alkylene-(substituted or unsubstituted aryl), and            —C₁-C₄alkylene-(substituted or unsubstituted heteroaryl); or        -   two R⁹ groups attached to the same N atom are taken together            with the N atom to which they are attached to form a            substituted or unsubstituted C₂-C₁₀heterocycloalkyl;        -   R¹⁰ is substituted or unsubstituted C₁-C₆alkyl, substituted            or unsubstituted C₁-C₆heteroalkyl, substituted or            unsubstituted C₁-C₆fluoroalkyl, a substituted or            unsubstituted C₃-C₁₀cycloalkyl, a substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or            unsubstituted aryl, a substituted or unsubstituted benzyl, a            substituted or unsubstituted heteroaryl,            —C₁-C₄alkylene-(substituted or unsubstituted            C₃-C₁₀cycloalkyl), —C₁-C₄alkylene-(substituted or            unsubstituted C₂-C₁₀heterocycloalkyl),            —C₁-C₄alkylene-(substituted or unsubstituted aryl), or            —C₁-C₄alkylene-(substituted or unsubstituted heteroaryl);        -   R¹¹ is H or C₁-C₄alkyl.

In some embodiments, X is S; ring B is phenyl; R⁴ is H, halogen, —CN,—OH, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, or C₁-C₆alkoxy; R⁵is halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰,—S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂, —C(═O)N(R⁹)₂, substituted orunsubstituted C₁-C₁₀alkyl, substituted or unsubstitutedC₁-C₁₀fluoroalkyl, substituted or unsubstituted C₁-C₁₀fluoroalkoxy,substituted or unsubstituted C₁-C₁₀alkoxy, substituted or unsubstitutedC₁-C₁₀heteroalkyl, substituted or unsubstituted C₃-C₁₀cycloalkyl,substituted or unsubstituted C₂-C₁₀heterocycloalkyl, substituted orunsubstituted phenyl, substituted or unsubstituted monocyclicheteroaryl, or -L¹-L²-R⁶; L¹ is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NH—,—C(═O)—, —C(═O)NH—, or —S(═O)₂NH—; L² is substituted or unsubstitutedC₁-C₆alkylene, substituted or unsubstituted C₁-C₆fluoroalkylene orsubstituted or unsubstituted C₁-C₆heteroalkylene; R⁶ is —CN, —NO₂, —OH,—OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —CO₂R⁹, —C(═O)N(R⁹)₂,substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted orunsubstituted C₂-C₁₀heterocycloalkyl, substituted or unsubstitutedmonocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl,or substituted or unsubstituted aryl.

In some embodiments, each R^(A) is independently selected from H,halogen, —CN, —NO₂, —OH, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —CO₂R⁹,—C(═O)N(R⁹)₂, C₁-C₆alkyl, and C₆alkoxy.

In some embodiments, described herein is a compound of Formula (VIIIa),or a pharmaceutically acceptable salt, or N-oxide thereof:

-   -   wherein,    -   both R¹ are taken together with the carbon atom to which they        are attached to form a substituted or unsubstituted        C₃-C₆cycloalkyl or a substituted or unsubstituted        C₂-C₆heterocycloalkyl;    -   or    -   each R¹ is independently H, —OH, C₁-C₆alkyl, C₁-C₆alkoxy, or        C₁-C₆fluoroalkyl;    -   X is O or S;    -   R^(A) is C₁-C₆alkyl;    -   ring B is phenyl, naphthyl, monocyclic heteroaryl, or bicyclic        heteroaryl;    -   n is 0, 1, or 2;    -   R⁴ is H, halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,        —S(═O)₂R¹⁰, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy,        C₁-C₆alkoxy, or C₁-C₆heteroalkyl;    -   R⁵ is halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,        —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰,        —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂,        —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰, —NR¹¹C(═O)OR¹⁰,        C₁-C₁₀alkyl, C₁-C₁₀fluoroalkyl, C₁-C₁₀fluoroalkoxy,        C₁-C₁₀alkoxy, C₁-C₁₀heteroalkyl, substituted or unsubstituted        C₃-C₁₀cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted phenyl,        substituted or unsubstituted monocyclic heteroaryl, or        -L¹-L²-R⁶;        -   L¹ is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NH—, —C(═O)—,            —C(═O)NH—, —NHC(═O)—, —NHC(═O)O—, —NHC(═O)NH—, —C(═O)O—,            —OC(═O)—, —OC(═O)O—, —OC(═O)NH—, —NHS(═O)₂—, or —S(═O)₂NH—;        -   L² is C₁-C₆alkylene, C₁-C₆fluoroalkylene or            C₁-C₆heteroalkylene;        -   R⁶ is —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰,            —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰,            —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂, —OC(═O)N(R⁹)₂,            —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰, —NR¹¹C(═O)OR¹⁰, substituted            or unsubstituted C₃-C₁₀cycloalkyl, substituted or            unsubstituted C₂-C₁₀heterocycloalkyl, substituted or            unsubstituted monocyclic heteroaryl, substituted or            unsubstituted bicyclic heteroaryl, or substituted or            unsubstituted aryl;    -   each R⁹ is independently selected from H, C₁-C₆alkyl,        C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, a substituted or        unsubstituted C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted benzyl, a substituted or        unsubstituted heteroaryl, —C₁-C₄alkylene-(substituted or        unsubstituted C₃-C₁₀cycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted C₂-C₁₀heterocycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted aryl), and        —C₁-C₄alkylene-(substituted or unsubstituted heteroaryl); or    -   two R⁹ groups attached to the same N atom are taken together        with the N atom to which they are attached to form a substituted        or unsubstituted C₂-C₁₀heterocycloalkyl;    -   R¹⁰ is C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, a        substituted or unsubstituted C₃-C₁₀cycloalkyl, a substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, a substituted or        unsubstituted aryl, a substituted or unsubstituted benzyl, a        substituted or unsubstituted heteroaryl,        —C₁-C₄alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₄alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₄alkylene-(substituted or        unsubstituted aryl), or —C₁-C₄alkylene-(substituted or        unsubstituted heteroaryl);    -   R¹¹ is H or C₁-C₄alkyl.

In some embodiments, X is S; ring B is phenyl; R⁴ is H, halogen, —CN,—OH, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, or C₁-C₆alkoxy; R⁵is halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰,—S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂, —C(═O)N(R⁹)₂, C₁-C₁₀alkyl,C₁-C₁₀fluoroalkyl, C₁-C₁₀fluoroalkoxy, C₁-C₁₀alkoxy, C₁-C₁₀heteroalkyl,substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted orunsubstituted C₂-C₁₀heterocycloalkyl, substituted or unsubstitutedphenyl, substituted or unsubstituted monocyclic heteroaryl, or-L¹-L²-R⁶; L¹ is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NH—, —C(═O)—,—C(═O)NH—, or —S(═O)₂NH—; L² is C₁-C₆alkylene, C₁-C₆fluoroalkylene orC₁-C₆heteroalkylene; R⁶ is —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,—S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —CO₂R⁹, —C(═O)N(R⁹)₂, substituted orunsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, substituted or unsubstituted monocyclicheteroaryl, substituted or unsubstituted bicyclic heteroaryl, orsubstituted or unsubstituted aryl.

In some embodiments, R^(A) is C₁-C₆alkyl; both R¹ are taken togetherwith the carbon atom to which they are attached to form aC₃-C₆cycloalkyl; or each R¹ is independently C₁-C₄alkyl.

In some embodiments, the compound of Formula (VIII) has the structure ofFormula (IX):

In some embodiments, each R^(A) is independently selected from H,halogen, —OH, C₁-C₆alkyl, and C₁-C₆alkoxy.

In some embodiments, the compound of Formula (VIIIa) has the structureof Formula (IXa):

In some embodiments, each R⁹ is independently selected from H,C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, a substituted orunsubstituted C₃-C₆cycloalkyl, a substituted or unsubstitutedC₂-C₆heterocycloalkyl, a substituted or unsubstituted phenyl, asubstituted or unsubstituted benzyl, and a substituted or unsubstitutedmonocyclic heteroaryl; or two R⁹ groups attached to the same N atom aretaken together with the N atom to which they are attached to form asubstituted or unsubstituted C₂-C₆heterocycloalkyl; R^(II)) isC₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl, a substituted orunsubstituted C₃-C₆cycloalkyl, a substituted or unsubstitutedC₂-C₆heterocycloalkyl, a substituted or unsubstituted phenyl, or asubstituted or unsubstituted monocyclic heteroaryl.

In some embodiments, R⁵ is halogen, —CN, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,—S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂, —C(═O)NH(R⁹),C₁-C₁₀alkyl, C₁-C₁₀fluoroalkyl, C₁-C₁₀fluoroalkoxy, C₁-C₁₀alkoxy,C₁-C₁₀heteroalkyl, substituted or unsubstituted C₃-C₁₀cycloalkyl,substituted or unsubstituted C₂-C₁₀heterocycloalkyl, substituted orunsubstituted phenyl, substituted or unsubstituted monocyclicheteroaryl, or -L¹-L²-R⁶; L¹ is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NH—,—C(═O)—, —C(═O)NH—, or —S(═O)₂NH—; L² is C₁-C₄alkylene; R⁶ is —CN, —OH,—OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —CO₂R⁹, —C(═O)N(R⁹)₂,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₆heterocycloalkyl, substituted or unsubstitutedmonocyclic heteroaryl, or substituted or unsubstituted phenyl.

In some embodiments, R^(A) is —CH₃; both R¹ are taken together with thecarbon atom to which they are attached to form a cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl; or each R¹ is —CH₃; R⁵ ishalogen, —CN, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂,—C(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂, —C(═O)NH(R⁹), C₁-C₁₀alkyl,C₁-C₁₀fluoroalkyl, C₁-C₁₀fluoroalkoxy, C₁-C₁₀alkoxy, C₁-C₁₀heteroalkyl,substituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₆heterocycloalkyl, substituted or unsubstitutedphenyl, substituted or unsubstituted monocyclic heteroaryl, or-L¹-L²-R⁶; L¹ is absent, —O—, —S—, —S(O)—, —S(O)₂—, —NH—, —C(═O)—,—C(═O)NH—, or —S(═O)₂NH—; L² is C₁-C₄alkylene; R⁶ is substituted orunsubstituted C₂-C₆heterocycloalkyl, substituted or unsubstitutedmonocyclic heteroaryl, or substituted or unsubstituted phenyl.

In some embodiments, the compound of Formula (VIII) or Formula (VIIIa)has the following structure:

In some embodiments, R^(A) is H, halogen, —OH, C₁-C₆alkyl, orC₁-C₆alkoxy. In some embodiments, R^(A) is C₁-C₆alkyl. In someembodiments, R^(A) is —CH₃.

In some embodiments, R⁴ is H, halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹,—S(═O)R¹⁰, —S(═O)₂R¹⁰, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy,C₁-C₆alkoxy, or C₁-C₆heteroalkyl. In some embodiments, R⁴ is halogen. Insome embodiments, R⁴ is F.

In some embodiments, R⁵ is halogen, —CN, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰,—S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —CO₂R⁹, —C(═O)N(R⁹)₂, C₁-C₄alkyl,C₁-C₄fluoroalkyl, C₁-C₄fluoroalkoxy, C₁-C₄alkoxy. In some embodiments,R⁵ is —CO₂R⁹ or —C(═O)N(R⁹)₂. In some embodiments, R⁵ is —CO₂H,—C(═O)NH₂ or —C(═O)NH(CH₃).

In some embodiments, described herein is a compound of Formula (X), or apharmaceutically acceptable salt, solvate, N-oxide, metabolite orprodrug thereof:

-   -   wherein,    -   each R¹ is independently selected from H and —CH₃;    -   or both R¹ are taken together with the carbon atom to which they        are attached to form a cyclobutyl;    -   X is O or S;    -   X¹ is CH or N;    -   R^(A) is —CN or —C(═O)NH₂;    -   R⁵ is —CO₂H, or —C(═O)NH₂.

In some embodiments, described herein is a compound of Formula (X), or apharmaceutically acceptable salt, solvate, N-oxide, metabolite orprodrug thereof:

-   -   wherein,    -   each R¹ is independently selected from H and —CH₃;    -   or both R¹ are taken together with the carbon atom to which they        are attached to form a cyclobutyl;    -   X is O;    -   X¹ is CH or N;    -   R^(A) is —CN or —C(═O)NH₂;    -   R⁵ is —CO₂H, —C(═O)NH₂ or —C(═O)NH(CH₃).

In some embodiments, described herein is a compound of Formula (X), or apharmaceutically acceptable salt, solvate, N-oxide, metabolite orprodrug thereof:

-   -   wherein,    -   each R¹ is independently selected from H and —CH₃;    -   or both R¹ are taken together with the carbon atom to which they        are attached to form a cyclobutyl;    -   X is O or S;    -   X¹ is CH or N;    -   R^(A) is —C(═O)NH₂;    -   R⁵ is —CO₂H, —C(═O)NH₂ or —C(═O)NH(CH₃).

Throughout the specification, groups and substituents thereof can bechosen by one skilled in the field to provide stable moieties andcompounds.

In one aspect, compounds described herein include compounds in Table 1,or a pharmaceutically acceptable salt thereof, or N-oxide thereof:

TABLE 1 LCMS * Cmpd. Name Structure [M + 1]⁺ 1 5-(5-(3-Fluoro-4-hydroxyphenyl)-8-oxo-6- thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

2 5-(4-Hydroxyphenyl)-6-thioxo- 7-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin- 6-yl)-5,7-diazaspiro[3.4]octan- 8-one

435.4 3 Ethyl 4-(7-(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluorobenzoate

4 5-(5-(4-Bromo-3- fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)- 3- (trifluoromethyl)picolinonitrile

500.3 5 4-(7-(6-Cyano-5- methylpyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluoro-N-methylbenzamide

424.0 6 4-(3-(6-Cyano-5- methylpyridin-3-yl)-4-oxo-2- thioxo-1,3-diazaspiro[4.4]nonan-1-yl)-2- fluoro-N-methylbenzamide

438.1 7 3-Methyl-5-(5-(4-(5- methylfuran-2-yl)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7- yl)picolinonitrile

429.1 8 Ethyl 5-(7-(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluorobenzoate

493.4 9 5-(5-(Naphthalen-2-yl)-8-oxo- 6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

453.0 10 5-(5-(2-Cyanophenyl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

428.0 11 5-(5-(3-Cyanophenyl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

428.4 12 5-(5-(4-Cyanophenyl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

428.4 13 5-(5-([1,1′-Biphenyl]-4-yl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

479.5 14 5-(5-([1,1′-Biphenyl]-3-yl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

479.0 15 5-(5-([1,1′-Biphenyl]-2-yl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

479.0 16 5-(8-Oxo-5-(4-(pyridin-2- yl)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

480.1 17 5-(8-Oxo-5-(4-(pyridin-3- yl)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

480.1 18 5-(8-Oxo-5-(4-(pyridin-4- yl)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

480.1 19 5-(8-Oxo-5-(pyridin-3-yl)-6- thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

404.4 20 5-(8-Oxo-6-thioxo-5-(o-tolyl)- 5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

417.5 21 5-(8-Oxo-6-thioxo-5-(m-tolyl)- 5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

417.5 22 5-(8-Oxo-6-thioxo-5-(p-tolyl)- 5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

417.5 23 ^(a) 5-(8-Oxo-5-(2- phenoxyphenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

495.5 24 5-(8-Oxo-5-(3- phenoxyphenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

495.5 25 5-(8-Oxo-5-(4- phenoxyphenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

495.5 26 5-(5-(2-Fluorophenyl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

421.5 27 5-(5-(3-Fluorophenyl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

421.5 28 5-(5-(4-Fluorophenyl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

421.5 29 5-(5-(4-Fluoro-2- methoxyphenyl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

451.5 30 6-Thioxo-5-(p-tolyl)-7-(3- (trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin- 6-yl)-5,7-diazaspiro[3.4]octan- 8-one

433.5 31 3-Methyl-5-(8-oxo-6-thioxo-5- (p-tolyl)-5,7-diazaspiro[3.4]octan-7- yl)picolinonitrile

363.5 32 5-(5-(4-Fluoro-3- methoxyphenyl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

451.0 33 5-(4,4-Dimethyl-5-oxo-2- thioxo-3-(p-tolyl)imidazolidin-1-yl)-3- (trifluoromethyl)picolinonitrile

405.5 34 6-(8-Oxo-6-thioxo-5-(p-tolyl)- 5,7-diazaspiro[3.4]octan-7-yl)-2- (trifluoromethyl)nicotinonitrile

417.5 35 4-(7-(5-Cyano-6- (trifluoromethyl)pyridin-2-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenzamide

478.5 36 5-(8-Oxo-6-thioxo-5-(p-tolyl)- 5,7-diazaspiro[3.4]octan-7-yl)quinoline-8-carbonitrile

399.6 37 4-(7-(8-Cyanoquinolin-5-yl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluoro-N-methylbenzamide

460.6 38 5-(5-(4-Fluoro-2- hydroxyphenyl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

437.5 39 5-(8-Oxo-5-(4-(pyridin-3- yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

496.1 40 5-(8-Oxo-5-(4-(pyridin-4- yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

496.4 41 5-(8-Oxo-5-(4-(pyridin-2- yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

496.6 42 5-(8-Oxo-5-(4-(pyrimidin-5- yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

496.9 43 4-(3-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide

466.5 44 5-(8-Oxo-6-thioxo-5-(4- (trifluoromethoxy)phenyl)-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

487.5 45 5-(8-Oxo-6-thioxo-5-(3- (trifluoromethoxy)phenyl)-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

487.5 46 5-(8-Oxo-6-thioxo-5-(4- (trifluoromethyl)phenyl)-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

471.5 47 4-(3-(6-Cyano-5- methylpyridin-3-yl)-5,5- dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2- fluoro-N-methylbenzamide

412.5 48 5-(8-Oxo-5-phenyl-6-thioxo- 5,7-diazaspiro[3.4]octan-7-yl)- 3-(trifluoromethyl)picolinonitrile

403.5 49 5-(5-(3-Fluoro-4- methylphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)- 3- (trifluoromethyl)picolinonitrile

435.5 50 5-(5-(2-Fluoro-4- methylphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)- 3- (trifluoromethyl)picolinonitrile

435.5 51 5-(5-(Isoquinolin-6-yl)-8-oxo- 6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

454.6 52 5-(5-(Isoquinolin-7-yl)-8-oxo- 6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

454.6 53 5-(5-Cyclohexyl-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

409.6 54 5-(5-(3-Fluoro-4- hydroxyphenyl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- methylpicolinonitrile

383.0 55 5-(5-(3-Fluoro-4- hydroxyphenyl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-7- yl)quinoline-8-carbonitrile

419.0 56 5-(5-(4-Cyano-3-fluorophenyl)- 8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

446.6 57 3-Chloro-5-(8-oxo-6-thioxo-5- (p-tolyl)-5,7-diazaspiro[3.4]octan-7- yl)picolinonitrile

383.0 58 4-(7-(5-Chloro-6-cyanopyridin- 3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluoro-N-methylbenzamide

444.0 59 3-Methoxy-5-(8-oxo-6-thioxo- 5-(p-tolyl)-5,7-diazaspiro[3.4]octan-7- yl)picolinonitrile

379.0 60 4-(7-(6-Cyano-5- methoxypyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluoro-N-methylbenzamide

440.0 61 6-Thioxo-5-(p-tolyl)-7-(3- (trifluoromethyl)-[2,3′-bipyridin]-5-yl)-5,7- diazaspiro[3.4]octan-8-one

469.0 62 7-(Imidazo[1,2-a]pyridin-6-yl)- 6-thioxo-5-(p-tolyl)-5,7-diazaspiro[3.4]octan-8-one

363.0 63 5-(5-(4-Hydroxyphenyl)-8-oxo- 6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

419.9 64 5-(5-(2-Fluoro-4- hydroxyphenyl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

437.8 65 4-(8-Oxo-6-thioxo-5-(p-tolyl)- 5,7-diazaspiro[3.4]octan-7-yl)isoquinoline-1-carbonitrile

399.0 66 4-(7-(1-Cyanoisoquinolin-4- yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluoro-N-methylbenzamide

460.0 67 5-(5-(3- (Hydroxymethyl)phenyl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

433.0 68 5-(5-(2- (Hydroxymethyl)phenyl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

433.0 69 5-(5-(4- (Hydroxymethyl)phenyl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

433.1 70 5-(5-(4-Cyano-2-fluorophenyl)- 8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

445.9 71 Methyl 4-(7-(6-cyano-5- methylpyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-3- fluorobenzoate

425.0 72 5-(5-(2,3-Difluorophenyl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

438.9 73 5-(5-(2,6-Difluorophenyl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

438.9 74 5-(5-(2,5-Difluorophenyl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

439.0 75 5-(8-Oxo-6-thioxo-5-(2,3,6- trifluorophenyl)-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

456.9 76 5-(5-(2,4-Difluorophenyl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

438.9 77 5-(5-(4-Hydroxyphenyl)-8-oxo- 6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- methylpicolinonitrile

365.0 78 4-(7-(6-Cyano-5- methylpyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-5-yl)-N- methylbenzamide

406.1 79 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-N- methylbenzamide

460.0 80 5-(5-(4- (Methylsulfonyl)phenyl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

481.0 81 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5- yl)benzenesulfonamide

482.0 82 4-(8-Oxo-6-thioxo-5-(p-tolyl)- 5,7-diazaspiro[3.4]octan-7-yl)pyrazolo[1,5-a]pyridine-7- carbonitrile

388.0 83 4-(7-(7-Cyanopyrazolo[1,5- a]pyridin-4-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)- 2-fluoro-N-methylbenzamide

449.0 84 5-(5-(4-Methylbenzyl)-8-oxo- 6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

431.0 85 5-(5-(4-Methylphenethyl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

445.0 86 5-(5-(4-(3- Hydroxypropyl)phenyl)-8-oxo- 6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

461.1 87 5-(5-(1H-Indazol-5-yl)-8-oxo- 6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

443.7 88 5-(5-(1H-Indazol-6-yl)-8-oxo- 6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

443.7 89 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-3-fluoro-N-methylbenzamide

478.3 90 5-(5-(4-(4-Methylpiperazin-1- yl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

501.1 91 5-(8-Oxo-5-(4-((2-(pyridin-4- yl)ethyl)sulfonyl)phenyl)-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

572.1 92 5-(5-(4-((Methyl(pyridin-4- ylmethyl)amino)methyl)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

537.1 93 5-(5-(4-((4-Methylpiperazin-1- yl)methyl)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

515.1 94 4-(8-Oxo-6-thioxo-5-(p-tolyl)- 5,7-diazaspiro[3.4]octan-7-yl)-1-naphthonitrile

398.6 95 4-(7-(4-Cyanonaphthalen-1-yl)- 8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluoro-N-methylbenzamide

459.5 96 3-Methyl-5-(5-(4-(6- methylpyridin-3-yl)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7- yl)picolinonitrile

440.0 97 3-Methyl-5-(5-(4-(4- methylpyridin-3-yl)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7- yl)picolinonitrile

440.1 98 3-Methyl-5-(5-(4-(5- methylpyridin-3-yl)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7- yl)picolinonitrile

440.1 99 3-Methyl-5-(5-(4-(2- methylpyridin-3-yl)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7- yl)picolinonitrile

440.0 100 5-(3-(4-Hydroxyphenyl)-4,4- dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3- (trifluoromethyl)picolinonitrile

407.0 101 5-(3-(4-Hydroxyphenyl)-4,4- dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3- methylpicolinonitrile

353.0 102 3-Methyl-5-(5-(4-methyl(1- methylpiperidin-4-yl)amino)phenyl)-8-oxo-6- thioxo-5,7- diazaspiro[3.4]octan-7-yl)picolinonitrile

475.1 103 3-Methyl-5-(8-oxo-5-(4- (pyrimidin-5-yl)phenyl)-6- thioxo-5,7-diazaspiro[3.4]octan-7- yl)picolinonitrile

427.0 104 4-(7-(6-Cyano-5- methylpyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-5-yl)-3- fluoro-N-methylbenzamide

424.0 105 5-(5-(4-(5-Fluoropyridin-3- yl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- methylpicolinonitrile

444.0 106 4-(7-(6-Cyano-5- methylpyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-5-yl)-N,2- dimethylbenzamide

419.9 107 4-(7-(6-Cyano-5- methylpyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- methoxy-N-methylbenzamide

436.0 108 2-Chloro-4-(7-(6-cyano-5- methylpyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-N- methylbenzamide

440.0 109 4-(7-(6-Cyano-5- methylpyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-5-yl)-N- methyl-2- (trifluoromethyl)benzamide

474.1 110 5-(5-(Naphthalen-1-yl)-8-oxo- 6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

453.0 111 3-Methyl-5-(8-oxo-5-(1- oxoisoindolin-5-yl)-6-thioxo-5,7-diazaspiro[3.4]octan-7- yl)picolinonitrile

404.1 112 3-Methyl-5-(8-oxo-5-(4- (tetrahydro-2H-pyran-4-yl)phenyl)-6-thioxo-5,7- diazaspiro[3.4]octan-7- yl)picolinonitrile

433.0 113 4-(7-(6-Cyano-5- (difluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenzamide

460.0 114 1-Methyl-4-(8-oxo-6-thioxo-5- (p-tolyl)-5,7-diazaspiro[3.4]octan-7-yl)-1H- pyrrole-2-carbonitrile

352.1 115 5-(8-Oxo-5-(4-(tetrahydro-2H- pyran-4-yl)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)- 3- (trifluoromethyl)picolinonitrile

487.1 116 5-(5-(4-(Furan-2-yl)phenyl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- methylpicolinonitrile

415.1 117 5-(3-Fluoro-4-hydroxyphenyl)- 6-thioxo-7-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin- 6-yl)-5,7-diazaspiro[3.4]octan- 8-one

453.5 118 5-(8-Oxo-5-(4-(piperazin-1- yl)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

487.1 119 tert-Butyl 4-(4-(7-(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5- yl)phenyl)piperazine-1-carboxylate

587.2 120 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-N-methylbenzenesulfonamide

518.0 121 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-N,N-dimethylbenzenesulfonamide

532.0 122 Methyl 4-(4-(7-(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5- yl)phenyl)butanoate

503.0 123 5-(5-(4-Fluoro-3- hydroxyphenyl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

437.5 124 5-(5-(4-(3-(4-Methylpiperazin- 1-yl)propyl)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

543.1 125 5-(5-(Benzo[d]oxazol-6-yl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

444.0 126 5-(5-(3-Fluoro-4-(2-(1-methyl- 1H-pyrazol-5-yl)ethoxy)phenyl)-8-oxo-6- thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

545.5 127 5-(5-(3-Fluoro-4-(2-(pyrrolidin- 1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

534.9 128 5-(5-(4-(Benzyloxy)-3- fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)- 3- (trifluoromethyl)picolinonitrile

527.6 129 5-(5-(4-((1-Methylpiperidin-4- yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)- 3- (trifluoromethyl)picolinonitrile

516.0 130 5-(5-(3-Fluoro-4-(2-(pyridin-2- yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

542.6 131 5-(5-(3-Fluoro-4-(2- methoxyethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

495.5 132 Ethyl 2-(4-(7-(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluorophenoxy)acetate

523.5 133 5-(5-(3-Fluoro-4-(4- methoxybutoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

523.6 134 5-(5-(3-Fluoro-4-((4,4,5,5,5- pentafluoropentyl)oxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

597.7 135 5-(5-(4-(3- (Benzyloxy)propoxy)-3-fluorophenyl)-8-oxo-6-thioxo- 5,7-diazaspiro[3.4]octan-7-yl)- 3-(trifluoromethyl)picolinonitrile

585.5 136 5-(5-(4-(4-(Benzyloxy)butoxy)- 3-fluorophenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

599.8 137 5-(5-(3-Fluoro-4-(2- methylphenethyl)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

555.8 138 5-(5-(3-Fluoro-4-(3- phenylpropoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

555.8 139 5-(5-(3-Fluoro-4-(3,3,4,4,4- pentafluorobutoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

583.4 140 5-(5-(3-Fluoro-4-(2- (naphthalen-1- yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

591.2 141 5-(5-(3-Fluoro-4-(2- (naphthalen-2- yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

591.2 142 5-(5-(3-Fluoro-4-(2-(pyridin-4- yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

542.7 143 5-(5-(3-Fluoro-4-(2- morpholinoethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

550.6 144 5-(5-(3-Fluoro-4-(2-(pyridin-3- yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

542.5 145 5-(5-(3-Fluoro-4-(3-(pyridin-3- yl)propoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

556.5 146 5-(5-(4-(2-(1H-Pyrrol-1- yl)ethoxy)-3-fluorophenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

530.5 147 5-(5-(3-Fluoro-4-(pyridin-2- ylmethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

528.8 148 5-(5-(3-Fluoro-4-(pyridin-3- ylmethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

528.5 149 5-(5-(3-Fluoro-4-(2-(4- methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6- thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

563.8 150 5-(5-(3-Fluoro-4-(3- morpholinopropoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

564.7 151 5-(5-(3-Fluoro-4-(4-((4,4,5,5,5-pentafluoropentyl)thio)butoxy) phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

685.5 152 5-(5-(3-Fluoro-4-(4-((4,4,5,5,5- pentafluoropentyl)sulfinyl)butoxy) phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

701.5 153 5-(5-(3-Fluoro-4-(3-((4,4,5,5,5-pentafluoropentyl)thio)propoxy) phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

671.8 154 5-(5-(3-Fluoro-4-(3-((4,4,5,5,5- pentafluoropentyl)sulfinyl)propoxy)phenyl)-8-oxo-6- thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

687.5 155 5-(4-(2-(Pyridin-2- yl)ethoxy)phenyl)-6-thioxo-7-(3-(trifluoromethyl)- [1,2,4]triazolo[4,3-b]pyridazin-6-yl)-5,7-diazaspiro[3.4]octan- 8-one

540.6 156 5-(5-(3-Fluoro-4-(pyridin-4- ylmethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

528.5 157 5-(5-(3-Fluoro-4-(3-(4- methylpiperazin-1-yl)propoxy)phenyl)-8-oxo-6- thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

577.5 158 5-(5-(4-Fluoro-3-(2-(pyridin-2- yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

542.1 159 5-(5-(4-Fluoro-3-(2-(pyridin-3- yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

542.0 160 5-(5-(4-Fluoro-3-(2-(pyridin-4- yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

542.5 161 5-(5-(3-(Benzyloxy)-4- fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)- 3- (trifluoromethyl)picolinonitrile

527.5 162 5-(5-(4-Fluoro-3- phenethoxyphenyl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

541.5 163 5-(5-(4-Fluoro-3-(3- phenylpropoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

555.5 164 5-(5-(4-Fluoro-3-(2- morpholinoethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

550.1 165 5-(5-(4-Fluoro-3-(3- morpholinopropoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

564.7 166 5-(5-(4-Fluoro-3-(2-(4- methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6- thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

563.5 167 5-(5-(4-Fluoro-3-(3-(4- methylpiperazin-1-yl)propoxy)phenyl)-8-oxo-6- thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

577.6 168 5-(5-(3-Fluoro-4-(2- methoxyethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3- methylpicolinonitrile

441.6 169 5-(5-(3-Fluoro-4-(2-(pyridin-2- yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3- methylpicolinonitrile

488.7 170 5-(5-(3-Fluoro-4-(2-(4- methypiperazin-1-yl)ethoxy)phenyl)-8-oxo-6- thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-methylpicolinonitrile

509.8 171 5-(5-(3-Fluoro-4-(2- methoxyethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7- yl)quinoline-8-carbonitrile

477.6 172 5-(5-(3-Fluoro-4-(2-(pyridin-2- yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7- yl)quinoline-8-carbonitrile

524.6 173 5-(5-(3-Fluoro-4-(2-(4- methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6- thioxo-5,7- diazaspiro[3.4]octan-7-yl)quinoline-8-carbonitrile

545.6 174 5-(5-(3-Fluoro-4-(2-(piperazin- 1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

549.9 175 5-(5-(3-Fluoro-4-(2- thiomorpholinoethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

566.8 176 5-(5-(3-Fluoro-4-(2-(pyrazin-2- yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

543.8 177 5-(5-(3-Fluoro-4-(2-(piperidin- 1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

548.8 178 5-(5-(4-(2-(4-Methylpiperazin- 1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

545.8 179 5-(5-(4-(2-Cyclohexylethoxy)- 3-fluorophenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

547.9 180 5-(5-(3-Fluoro-4-(2- (tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)-8-oxo-6- thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

549.8 181 5-(5-(2-Fluoro-4-(2- methoxyethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

495.7 182 5-(5-(2-Fluoro-4-(2-(4- methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6- thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

563.9 183 5-(5-(2-Fluoro-4-(2-(pyridin-2- yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

542.0 184 5-(5-(2-Fluoro-4-(3-(4- methylpiperazin-1-yl)propoxy)phenyl)-8-oxo-6- thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

577.1 185 5-(5-(3-Fluoro-4-(3-(pyrrolidin- 1-yl)propoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

548.1 186 5-(5-(4-(2-(1,1- Dioxidomorpholino)ethoxy)-3-fluorophenyl)-8-oxo-6- thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

598.0 187 5-(5-(2-Fluoro-4-(2-(piperidin- 1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

548.1 188 5-(5-(3-Fluoro-4- phenethoxyphenyl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

541.1 189 5-(5-(3-Fluoro-4-(2-(pyrimidin- 2-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

543.1 190 5-(5-(2-Fluoro-4-(1- methylpyridin-4-yl)oxy)phenyl)-8-oxo-6-thioxo- 5,7-diazaspiro[3.4]octan-7-yl)- 3-(trifluoromethyl)picolinonitrile

534.0 191 3-Methyl-5-(5-(4-((1- methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo- 5,7-diazaspiro[3.4]octan-7-yl)picolinonitrile

462.1 192 5-(5-(3-Fluoro-4-((1- methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo- 5,7-diazaspiro[3.4]octan-7-yl)-3-methylpicolinonitrile

480.1 193 5-(5-(3-Fluoro-4-((1- methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo- 5,7-diazaspiro[3.4]octan-7-yl)- 3-(trifluoromethyl)picolinonitrile

534.2 194 3-Methyl-5-(8-oxo-5-(4- ((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-6-thioxo-5,7- diazaspiro[3.4]octan-7- yl)picolinonitrile

449.0 195 3-Methyl-5-(8-oxo-5-(4- ((tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)-6-thioxo-5,7- diazaspiro[3.4]octan-7- yl)picolinonitrile

465.0 196 5-(4,4-Dimethyl-3-(4-((1- methylpiperidin-4-yl)oxy)phenyl)-5-oxo-2- thioxoimidazolin-1-yl)-3-(trifluoromethyl)picolinonitrile

504.1 197 5-(4,4-Dimethyl-3-(4-((1- methylpiperidin-4-yl)oxy)phenyl)-5-oxo-2- thioxoimidazolidin-1-yl)-3-methylpicolinonitrile

450.1 198 5-(8-Oxo-5-(4-((tetrahydro-2H- pyran-4-yl)oxy)phenyl)-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

503.0 199 3-Methyl-5-(8-oxo-6-thioxo-5- (4-(2-(4-(2,2,2-trifluoroethyl)piperazin-1- yl)ethoxy)phenyl)-5,7-diazaspiro[3.4]octan-7- yl)picolinonitrile

559.1 200 3-Methyl-5-(5-(4-(2-(4- methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6- thioxo-5,7- diazaspiro[3.4]octan-7-yl)picolinonitrile

491.2 201 5-(5-(4-((1,1- Dioxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)-8- oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- methylpicolinonitrile

497.0 202 5-(5-(4-(2-(4-Acetylpiperazin- 1-yl)ethoxy)-3-fluorophenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

591.9 203 5-(5-(3-Fluoro-4- methoxyphenyl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

451.4 204 5-(5-(4-Methoxyphenyl)-8-oxo- 6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

433.8 205 5-(5-(4-Methoxyphenyl)-8-oxo- 6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- methylpicolinonitrile

379.0 206 5-(8-Oxo-5-(4-(pyrimidin-2- yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

497.8 207 5-(8-Oxo-5-(4-(pyrazin-2- yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

496.9 208 5-(8-Oxo-5-(4-(pyrimidin-4- yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

497.1 209 3-Methyl-5-(8-oxo-5-(4- (pyrimidin-4-yloxy)phenyl)-6-thioxo-5,7- diazaspiro[3.4]octan-7- yl)picolinonitrile

443.0 210 3-Methyl-5-(8-oxo-5-(4- (piperidin-4-yloxy)phenyl)-6-thioxo-5,7- diazaspiro[3.4]octan-7- yl)picolinonitrile

448.1 211 5-(8-Oxo-5-(4-(piperidin-4- yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- (trifluoromethyl)picolinonitrile

502.2 212 5-(8-Oxo-5-(4-((1- propionylpiperidin-4-yl)oxy)phenyl)-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

558.1 213 5-(5-(4-((1-isobutyrylpiperidin- 4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

572.1 214 ethyl 4-(4-(7-(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5- yl)phenoxy)piperidine-1-carboxylate

574.0 215 5-(5-(4-((1-acetylpiperidin-4- yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)- 3-methylpicolinonitrile

490.0 216 5-(5-(4-((1-Ethylpiperidin-4- yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)- 3-methylpicolinonitrile

476.1 217 5-(5-(4-((1-(2- Hydroxyethyl)piperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo- 5,7-diazaspiro[3.4]octan-7-yl)-3-methylpicolinonitrile

492.1 218 5-(5-(4-((1-(2- hydroxyethyl)piperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo- 5,7-diazaspiro[3.4]octan-7-yl)- 3-(trifluoromethyl)picolinonitrile

546.1 219 5-(5-(4-((1- (methylsulfonyl)piperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo- 5,7-diazaspiro[3.4]octan-7-yl)- 3-(trifluoromethyl)picolinonitrile

580.1 220 5-(5-(4-((1-Isopropylpiperidin- 4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

544.0 221 Ethyl 2-(4-(4-(7-(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5- yl)phenoxy)piperidin-1-yl)acetate

588.1 222 4-(4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5- yl)phenoxy)piperidine-1-carboxamide

545.2 223 5-(5-(4-(2- Hydroxyethoxy)phenyl)-8-oxo- 6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3- methylpicolinonitrile

409.0 224 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluorobenzoic acid

225 4-(7-(6-Cyano-5- methylpyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluorobenzoic acid

411.0 226 5-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluorobenzoic acid

465.4 227 4-(4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5- yl)phenyl)butanoic acid

489.0 228 2-(4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluorophenoxy)aceticacid

495.5 229 5-(7-(6-Carbamoyl-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluorobenzoic acid

483.4 230 4-(4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5- yl)phenyl)-N-methylbutanamide

502.0 231 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluorobenzamide

464.0 232 4-(7-(6-Cyano-5- methylpyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluorobenzamide

410.0 233 4-(7-(6-Cyano-5- methypyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- methylbenzamide

406.1 234 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(2-(pyrrolidin-1- yl)ethyl)benzamide

561.1 235 N-Benzyl-4-(7-(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluorobenzamide

554.5 236 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(2-(pyridin-2- yl)ethyl)benzamide

569.5 237 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(3-(pyrrolidin-1- yl)propyl)benzamide

575.1 238 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(2-(pyridin-4- yl)ethyl)benzamide

569.5 239 5-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(2-(pyridin-2- yl)ethyl)benzamide

569.5 240 5-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(2-(pyridin-3- yl)ethyl)benzamide

569.5 241 5-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(2-(pyridin-4- yl)ethyl)benzamide

569.5 242 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(2-morpholinoethyl)benzamide

577.5 243 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(2-(4-methylpiperazin-1- yl)ethyl)benzamide

590.5 244 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(2-(pyridin-3- yl)ethyl)benzamide

569.5 245 Ethyl 2-(4-(7-(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluorobenzamido)acetate

550.5 246 Ethyl 3-(4-(7-(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluorobenzamido)propanoate

564.5 247 Ethyl 4-(4-(7-(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluorobenzamido)butanoate

578.5 248 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(2-methoxyethyl)benzamide

522.5 249 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(3-methoxypropyl)benzamide

536.5 250 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(2-methoxyethyl)-N- methylbenzamide

536.5 251 5-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(2-(pyrrolidin-1- yl)ethyl)benzamide

561.6 252 5-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(3-(pyrrolidin-1- yl)propyl)benzamide

575.1 253 5-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(2-morpholinoethyl)benzamide

577.6 254 5-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(2-(4-methylpiperazin-1- yl)ethyl)benzamide

590.6 255 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluoro-N-phenylbenzamide

540.5 256 N-(2-(4-Bromo-1-methyl-1H- pyrazol-5-yl)ethyl)-4-(7-(6-cyano-5-(trifluoromethyl) pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)- 2-fluorobenzamide

652.2 257 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluoro-N-phenethylbenzamide

568.5 258 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(3-phenylpropyl)benzamide

582.5 259 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(pyridin-4-ylmethyl)benzamide

555.5 260 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(thiophen-2-ylmethyl)benzamide

560.5 261 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(pyridin-2-yl)benzamide

541.5 262 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(pyridin-3-yl)benzamide

541.4 263 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(pyridin-4-yl)benzamide

541.4 264 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(pyridin-2-ylmethyl)benzamide

555.9 265 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(pyridin-3-ylmethyl)benzamide

556.1 266 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(furan-2-ylmethyl)benzamide

544.4 267 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-N-cyclopentyl-2-fluorobenzamide

532.5 268 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(3-morpholinopropyl)benzamide

591.0 269 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(3-(4-methylpiperazin-1- yl)propyl)benzamide

604.0 270 5-(5-(3-Fluoro-4-(pyrrolidine- 1-carbonyl)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

518.0 271 5-(5-(3-Fluoro-4-(morpholine- 4-carbonyl)phenyl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

534.0 272 4-(7-(6-Cyano-5- methylpyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluoro-N-phenylbenzamide

486.8 273 N-Benzyl-4-(7-(6-cyano-5- methylpyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluorobenzamide

500.8 274 4-(7-(6-Cyano-5- methylpyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(thiophen-2- ylmethyl)benzamide

506.8 275 4-(7-(6-Cyano-5- methylpyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(3-(pyrrolidin-1-yl)propyl)benzamide

521.9 276 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(1-methylpiperidin-4- yl)benzamide

561.1 277 N-Butyl-4-(7-(6-cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluorobenzamide

520.0 278 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluoro-N-propylbenzamide

506.1 279 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluoro-N-isopropylbenzamide

506.1 280 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluoro-N-isobutylbenzamide

520.0 281 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(prop-2-yn-1-yl)benzamide

502.0 282 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluoro-N-isopentylbenzamide

532.1 283 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-N- (cyclopentylmethyl)-2-fluorobenzamide

546.0 284 4-(7-(6-Cyano-5- 8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-N- cyclopropyl-2-fluorobenzamide

504.0 285 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(2-hydroxy-2-methylpropyl)benzamide

519.0 (—OH) 286 N-(tert-Butyl)-4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)- 8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluorobenzamide

520.0 287 N-(2-Chlorobenzyl)-4-(7-(6- cyano-5-(trifluoromethyl)pyridin-3-yl)- 8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluorobenzamide

588.4 288 N-(3-Chlorobenzyl)-4-(7-(6- cyano-5-(trifluoromethyl)pyridin-3-yl)- 8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluorobenzamide

588.4 289 N-(4-Chlorobenzyl)-4-(7-(6- cyano-5-(trifluoromethyl)pyridin-3-yl)- 8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluorobenzamide

588.4 290 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(pyrazin-2-ylmethyl)benzamide

556.1 291 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluoro-N-((5-methylfuran-2- yl)methyl)benzamide

558.2 292 4-(4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5- yl)phenyl)-N-phenylbutanamide

564.0 293 4-(7-(6-Cyano-5- methylpyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(4- fluorobenzyl)benzamide

518.1 294 N-(2-Chlorophenyl)-4-(7-(6- cyano-5-methylpyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluorobenzamide

520.1 295 N-(3-Chlorophenyl)-4-(7-(6- cyano-5-methylpyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluorobenzamide

520.1 296 N-(4-Chlorophenyl)-4-(7-(6- cyano-5-methylpyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluorobenzamide

520.1 297 4-(7-(6-Cyano-5- methylpyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(2- fluorophenyl)benzamide

504.2 298 4-(7-(6-Cyano-5- methylpyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluorophenyl)benzamide

504.1 299 4-(7-(6-Cyano-5- methylpyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(4- fluorophenyl)benzamide

503.1 300 4-(7-(6-cyano-5-methylpyridin- 3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(oxazol-2- yl)benzamide

477.1 301 4-(7-(6-Cyano-5- methylpyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(thiazol-2- yl)benzamide

493.1 302 4-(7-(6-Cyano-5- methylpyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(1-methyl-1H-pyrazol-5-yl)benzamide

490.9 303 4-(7-(6-Cyano-5- methylpyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(1-methyl-1H-pyrazol-3-yl)benzamide

490.2 304 4-(7-(6-Cyano-5- methylpyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(6-methylpyridin-3- yl)benzamide

501.2 305 4-(7-(6-Cyano-5- methylpyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(5-fluoropyridin-3- yl)benzamide

505.1 306 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(3-hydroxypropyl)benzamide

521.9 307 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-N- (3-(cyclopentyl(methyl)amino) propyl)-2-fluorobenzamide

603.2 308 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(3-(2-oxopyrrolidin-1- yl)propyl)benzamide

589.0 309 5-(5-(3-Fluoro-4-(2-(4- methylpiperazin-1-yl)-2-oxoethoxy)phenyl)-8-oxo-6- thioxo-5,7- diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

577.1 310 4-(7-(6-Cyano-5- methylpyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluoro-N-(tetrahydro-2H-pyran-4-yl)benzamide

494.1 311 4-(7-(6-Cyano-5- methylpyridin-3-yl)-8-oxo-6- thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2- fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide

508.0 312 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-6,8-dioxo-5,7- diazaspiro[3.4]octan-5-yl)-2- fluoro-N-methylbenzamide

462.6 313 4-(7-(6-Cyano-5- (trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]octan-5-yl)-N-(3-(3,3-difluoropyrrolidin-1- yl)propyl)-2-fluorobenzamide

611.1 * mass spectrometric data

Compounds disclosed herein are AR modulators. In specific embodiments,compounds disclosed herein are AR inverse agonists, AR antagonists, ARdegraders, AR trafficking modulators and/or AR DNA-binding inhibitors.In some embodiments, compounds disclosed herein are AR inverse agonists.In some embodiments, compounds disclosed herein are AR antagonists. Insome embodiments, compounds disclosed herein are AR degraders. In someembodiments, compounds disclosed herein are AR trafficking modulators.In some embodiments, compounds disclosed herein are AR DNA-bindinginhibitors. The overall profile of an AR modulator for the treatment ofprostate cancer includes one or more of the foregoing profiles of an ARmodulator.

In some embodiments, compounds disclosed herein have the followingproperties: full AR antagonist in prostate cancer cells, inverse ARagonist in prostate cancer cells, no AR agonist activity in prostatecancer cells, AR Degrader activity in prostate cancer cells, noantagonist or agonist or degrader activity in non-prostate cancer cells,inhibition of prostate cancer growth.

In some embodiments, compounds disclosed herein have the followingproperties: full AR antagonist in prostate cancer cells, inverse ARagonist in prostate cancer cells, no AR agonist activity in prostatecancer cells, AR Degrader activity in prostate cancer cells, andinhibition of prostate cancer growth.

In some embodiments, compounds disclosed herein have the followingproperties: full AR antagonist in prostate cancer cells, inverse ARagonist in prostate cancer cells, no AR agonist activity in prostatecancer cells, inhibition of prostate cancer growth

In some embodiments, compounds disclosed herein have the followingproperties: full AR antagonist in prostate cancer cells, no AR agonistactivity in prostate cancer cells, inhibition of prostate cancer growth

In some embodiments, compounds disclosed herein have the followingproperties: AR Trafficking Modulator, no AR agonist activity in prostatecancer cells, no antagonist or agonist or degrader activity innon-prostate cancer cells, inhibition of prostate cancer growth

In some embodiments, compounds disclosed herein have the followingproperties: AR Trafficking Modulator, no AR agonist activity in prostatecancer cells, inhibition of prostate cancer growth.

In some embodiments, the compound of Formula (I), (Ia), (II), (III),(IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) has minimalpro-convulsant activity and/or minimal impact on seizure threshold.

In some embodiments, the compound of Formula (I), (Ia), (II), (III),(IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) displaysminimal modulation of the GABA-gated chloride channel.

In some embodiments, the compound of Formula (I), (Ia), (II), (III),(IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) displaysminimal binding to the GABA-gated chloride channel.

In some embodiments, the compound of Formula (I), (Ia), (II), (III),(IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) has minimalantagonism of the GABA-gated chloride channel.

In some embodiments, the compound of Formula (I), (Ia), (II), (III),(IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) is anandrogen receptor modulator with minimal interaction with a GABA-gatedchloride channel.

In some embodiments, the compound of Formula (I), (Ia), (II), (III),(IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) is anandrogen receptor modulator with minimal interaction with theGABA_(A)-gated chloride channel.

GABA assays are known and include, but are not limited to, thosedescribed in Ashok K. Mehta and Maharaj K. Ticku “Characterization ofthe Picrotoxin Site of GABA_(A) Receptors” Current Protocols inPharmacology (2000) 1.18.1-1.18.17; Copyright © 2000 by John Wiley &Sons, Inc., which is herein incorporated by reference.

In some embodiments, described herein is a method of treating cancer ina mammal comprising administering to the mammal a therapeuticallyeffective amount of a compound, wherein the compound: a) is an androgenreceptor inverse agonist; androgen receptor antagonist; is an androgenreceptor degrader; is an androgen receptor trafficking modulator; is anandrogen receptor DNA-binding inhibitor; or combinations thereof; and b)has minimal pro-convulsant activity and/or minimal impact on seizurethreshold; displays minimal modulation of the GABA-gated chloridechannel; displays minimal binding to the GABA-gated chloride channel;has minimal antagonism of the GABA-gated chloride channel; has minimalinteraction with a GABA-gated chloride channel; or combinations thereof.

In some embodiments, the compound has minimal interaction with theGABA_(A)-gated chloride channel. In some embodiments, the cancer isprostate cancer. In some embodiments, the cancer is hormone refractoryprostate cancer. In some embodiments, the compound is a compound ofFormula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa),(IX), (IXa) or (X), or a pharmaceutically acceptable salt thereof orN-oxide thereof.

In some embodiments, described herein is a method of identifying anandrogen receptor modulator comprising: 1) testing a compound forandrogen receptor modulatory activity in an appropriate assay; and 2)testing the same compound for activity on the GABA-gated chloridechannel in an appropriate in vitro or in vivo assay; wherein thecompound is an androgen receptor modulator if it exhibits activity in 1)and exhibits any one of the following in 2): displays minimal modulationof the GABA-gated chloride channel; displays minimal binding to theGABA-gated chloride channel; has minimal antagonism of the GABA-gatedchloride channel; or has minimal interaction with the GABA-gatedchloride channel.

Synthesis of Compounds

Compounds of Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII),(VIII), (VIIIa), (IX), (IXa) and (X) described herein are synthesizedusing standard synthetic techniques or using methods known in the art incombination with methods described herein. In additions, solvents,temperatures and other reaction conditions presented herein may vary.

The starting material used for the synthesis of the compounds of Formula(I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX),(IXa) and (X) are either synthesized or obtained from commercialsources, such as, but not limited to, Sigma-Aldrich, Fluka, AcrosOrganics, Alfa Aesar, and the like. The compounds described herein, andother related compounds having different substituents are synthesizedusing techniques and materials described herein or otherwise known,including those found in March, ADVANCED ORGANIC CHEMISTRY 4^(th) Ed.,(Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4^(th) Ed.,Vols. A and B (Plenum 2000, 2001), and Green and Wuts, PROTECTIVE GROUPSIN ORGANIC SYNTHESIS 3^(rd) Ed., (Wiley 1999). General methods for thepreparation of compounds can be modified by the use of appropriatereagents and conditions for the introduction of the various moietiesfound in the formulae as provided herein.

In some embodiments, the compounds of Formula (I), (Ia), (II), (III),(IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) and (X) areprepared as outlined in the following Scheme.

In some embodiments, amines of structure I are treated with ketones oraldehydes R¹—C(═O)—R¹ in the presence of NaCN, in a suitable solvent toprovide compounds of structure II. In some embodiments, the suitablesolvent is acetic acid. In some embodiments, the reaction is performedat a temperature from about 25° C. to about 80° C.

In some embodiments, compounds of structure II are treated withthiophosgene and compounds of structure III in a suitable solvent,followed by treated with an acid to provide thiohydantions of structureIV. In some embodiments, the suitable solvent is dimethylacetamide. Insome embodiments, the reaction is heated to about 60° C. In someembodiments, treatment with an acid encompasses treatment withhydrochloric acid. In some embodiments, treatment with an acidencompasses treatment with HCl, MeOH, at reflux for 2 h.

In some embodiments, compounds disclosed herein are prepared as outlinedin Scheme 2.

In some embodiments, compounds of structure V are elaborated intocompounds of structure VI by reacting compounds of structure V withelectrophiles or nucleophiles in the presence of a coupling agent. Forexample, in some embodiments, compounds of structure V are treated withcompounds such as R⁶-L²—OH in the presence of DIAD and PPh₃ in asuitable solvent to provide compounds of structure VI. In someembodiments, the suitable solvent is tetrahydrofurn.

In some embodiments, compounds disclosed herein are prepared as outlinedin Scheme 3.

Treatment of esters of structure VII with a suitable base in a suitablesolvent provides carboxylic acids of structure VIII. In someembodiments, the suitable base is lithium hydroxide. In someembodiments, the suitable solvent is tetrahydrofuran. Carboxylic acidsof structure VIII are then coupled with a variety of agents to providecompounds disclosed herein. In some embodiments, carboxylic acids ofstructure VIII are treated with amines R⁶-L²-NH₂ in the presence of acoupling reagent to provide amides of structure IX. In some embodiments,carboxylic acids of structure VIII are treated with alcohols R⁶-L²-OH inthe presence of a coupling reagent to provide esters as describedherein. In some embodiments, the coupling reagent is EDC, DCC, BOP, HATUor the like. In some embodiments, the coupling reaction is performed ina solvent selected from dichloromethane, dichloroethane,tetrahydrofuran, dimethoxyethane, dimethylformamide or the like in thepresence of a base. Suitable bases include, but are not limited to,triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine orthe like.

In one aspect, compounds of Formula (I), (Ia), (II), (III), (IV), (V),(VI), (VII), (VIII), (VIIIa), (IX), (IXa) and (X) are synthesized asoutlined in the Examples.

Throughout the specification, groups and substituents thereof are chosenby one skilled in the field to provide stable moieties and compounds.

A detailed description of techniques applicable to the creation ofprotecting groups and their removal are described in Greene and Wuts,Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, NewYork, N.Y., 1999, and Kocienski, Protective Groups, Thieme Verlag, NewYork, N.Y., 1994, which are incorporated herein by reference for suchdisclosure.

Further Forms of Compounds

In one aspect, compounds of Formula (I), (Ia), (II), (III), (IV), (V),(VI), (VII), (VIII), (VIIIa), (IX), (IXa) and (X) possess one or morestereocenters and each stereocenter exists independently in either the Ror S configuration. The compounds presented herein include alldiastereomeric, enantiomeric, and epimeric forms as well as theappropriate mixtures thereof. The compounds and methods provided hereininclude all cis, trans, syn, anti, entgegen (E), and zusammen (Z)isomers as well as the appropriate mixtures thereof. In certainembodiments, compounds of Formula (I), (Ia), (II), (III), (IV), (V),(VI), (VII), (VIII), (VIIIa), (IX), (IXa) and (X) are prepared as theirindividual stereoisomers by reacting a racemic mixture of the compoundwith an optically active resolving agent to form a pair ofdiastereoisomeric compounds/salts, separating the diastereomers andrecovering the optically pure enantiomers. In some embodiments,resolution of enantiomers is carried out using covalent diastereomericderivatives of the compounds described herein. In another embodiment,diastereomers are separated by separation/resolution techniques basedupon differences in solubility. In other embodiments, separation ofsteroisomers is performed by chromatography or by the formingdiastereomeric salts and separation by recrystallization, orchromatography, or any combination thereof. Jean Jacques, Andre Collet,Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John WileyAnd Sons, Inc., 1981. In some embodiments, stereoisomers are obtained bystereoselective synthesis.

The methods and compositions described herein include the use ofamorphous forms as well as crystalline forms (also known as polymorphs).In one aspect, compounds described herein are in the form ofpharmaceutically acceptable salts. As well, active metabolites of thesecompounds having the same type of activity are included in the scope ofthe present disclosure. In addition, the compounds described herein canexist in unsolvated as well as solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. The solvatedforms of the compounds presented herein are also considered to bedisclosed herein.

In some embodiments, compounds described herein are prepared asprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they may be easier to administer than the parent drug. Theymay, for instance, be bioavailable by oral administration whereas theparent is not. The prodrug may also have improved solubility inpharmaceutical compositions over the parent drug. In some embodiments,the design of a prodrug increases the effective water solubility. Anexample, without limitation, of a prodrug is a compound describedherein, which is administered as an ester (the “prodrug”) to facilitatetransmittal across a cell membrane where water solubility is detrimentalto mobility but which then is metabolically hydrolyzed to the carboxylicacid, the active entity, once inside the cell where water-solubility isbeneficial. A further example of a prodrug might be a short peptide(polyaminoacid) bonded to an acid group where the peptide is metabolizedto reveal the active moiety. In certain embodiments, upon in vivoadministration, a prodrug is chemically converted to the biologically,pharmaceutically or therapeutically active form of the compound. Incertain embodiments, a prodrug is enzymatically metabolized by one ormore steps or processes to the biologically, pharmaceutically ortherapeutically active form of the compound.

In one aspect, prodrugs are designed to alter the metabolic stability orthe transport characteristics of a drug, to mask side effects ortoxicity, to improve the flavor of a drug or to alter othercharacteristics or properties of a drug. By virtue of knowledge ofpharmacokinetic, pharmacodynamic processes and drug metabolism in vivo,once a pharmaceutically active compound is known, the design prodrugs ofthe compound is possible. (see, for example, Nogrady (1985) MedicinalChemistry A Biochemical Approach, Oxford University Press, New York,pages 388-392; Silverman (1992), The Organic Chemistry of Drug Designand Drug Action, Academic Press, Inc., San Diego, pages 352-401,Rooseboom et al., Pharmacological Reviews, 56:53-102, 2004; Aesop Cho,“Recent Advances in Oral Prodrug Discovery”, Annual Reports in MedicinalChemistry, Vol. 41, 395-407, 2006; T. Higuchi and V. Stella, Pro-drugsas Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series).

Prodrug forms of the herein described compounds, wherein the prodrug ismetabolized in vivo to produce a compound of Formula (I), (Ia), (II),(III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) asset forth herein are included within the scope of the claims. In somecases, some of the herein-described compounds may be a prodrug foranother derivative or active compound.

In some embodiments, sites on the aromatic ring portion of compounds ofFormula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa),(IX), (IXa) and (X) are susceptible to various metabolic reactionsTherefore incorporation of appropriate substituents on the aromatic ringstructures will reduce, minimize or eliminate this metabolic pathway. Inspecific embodiments, the appropriate substituent to decrease oreliminate the susceptibility of the aromatic ring to metabolic reactionsis, by way of example only, a halogen, or an alkyl group.

In another embodiment, the compounds described herein are labeledisotopically (e.g. with a radioisotope) or by another other means,including, but not limited to, the use of chromophores or fluorescentmoieties, bioluminescent labels, or chemiluminescent labels.

Compounds described herein include isotopically-labeled compounds, whichare identical to those recited in the various formulae and structurespresented herein, but for the fact that one or more atoms are replacedby an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopesthat can be incorporated into the present compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, forexample, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, 35S, ¹⁸F, ³⁶Cl. In one aspect,isotopically-labeled compounds described herein, for example those intowhich radioactive isotopes such as ³H and ¹⁴C are incorporated, areuseful in drug and/or substrate tissue distribution assays. In oneaspect, substitution with isotopes such as deuterium affords certaintherapeutic advantages resulting from greater metabolic stability, suchas, for example, increased in vivo half-life or reduced dosagerequirements.

In additional or further embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect.

“Pharmaceutically acceptable,” as used herein, refers a material, suchas a carrier or diluent, which does not abrogate the biological activityor properties of the compound, and is relatively nontoxic, i.e., thematerial may be administered to an individual without causingundesirable biological effects or interacting in a deleterious mannerwith any of the components of the composition in which it is contained.

The term “pharmaceutically acceptable salt” refers to a formulation of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In some embodiments, pharmaceuticallyacceptable salts are obtained by reacting a compound of Formula (I),(Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa)or (X) with acids. Pharmaceutically acceptable salts are also obtainedby reacting a compound of Formula (I), (Ia), (II), (III), (IV), (V),(VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) with a base to form asalt.

Compounds described herein may be formed as, and/or used as,pharmaceutically acceptable salts. The type of pharmaceutical acceptablesalts, include, but are not limited to: (1) acid addition salts, formedby reacting the free base form of the compound with a pharmaceuticallyacceptable: inorganic acid, such as, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid,and the like; or with an organic acid, such as, for example, aceticacid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaricacid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, toluenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, butyric acid, phenylacetic acid,phenylbutyric acid, valproic acid, and the like; (2) salts formed whenan acidic proton present in the parent compound is replaced by a metalion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium), analkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion. Insome cases, compounds described herein may coordinate with an organicbase, such as, but not limited to, ethanolamine, diethanolamine,triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine,tris(hydroxymethyl)methylamine. In other cases, compounds describedherein may form salts with amino acids such as, but not limited to,arginine, lysine, and the like. Acceptable inorganic bases used to formsalts with compounds that include an acidic proton, include, but are notlimited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide,sodium carbonate, sodium hydroxide, and the like.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and may beformed during the process of crystallization with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. Hydrates areformed when the solvent is water, or alcoholates are formed when thesolvent is alcohol. Solvates of compounds described herein can beconveniently prepared or formed during the processes described herein.In addition, the compounds provided herein can exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

Compounds described herein, such as compounds of Formula (I), (Ia),(II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) and(X), may be in various forms, including but not limited to, amorphousforms, milled forms and nano-particulate forms. In addition, compoundsdescribed herein include crystalline forms, also known as polymorphs.Polymorphs include the different crystal packing arrangements of thesame elemental composition of a compound. Polymorphs usually havedifferent X-ray diffraction patterns, melting points, density, hardness,crystal shape, optical properties, stability, and solubility. Variousfactors such as the recrystallization solvent, rate of crystallization,and storage temperature may cause a single crystal form to dominate.

CERTAIN TERMINOLOGY

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Unlessotherwise indicated, conventional methods of mass spectroscopy, NMR,HPLC, protein chemistry, biochemistry, recombinant DNA techniques andpharmacology are employed. In this application, the use of “or” or “and”means “and/or” unless stated otherwise. Furthermore, use of the term“including” as well as other forms, such as “include”, “includes,” and“included,” is not limiting. The section headings used herein are fororganizational purposes only and are not to be construed as limiting thesubject matter described.

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylgroup may be a saturated alkyl group or the the alkyl group may be anunsaturated alkyl group. The alkyl moiety, whether saturated orunsaturated, may be branched or straight chain. The “alkyl” group mayhave 1 to 10 carbon atoms (whenever it appears herein, a numerical rangesuch as “1 to 10” refers to each integer in the given range; e.g., “1 to10 carbon atoms” means that the alkyl group may consist of 1 carbonatom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10carbon atoms, although the present definition also covers the occurrenceof the term “alkyl” where no numerical range is designated). In oneaspect the alkyl is selected from the group consisting of methyl, ethyl,propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typicalalkyl groups include, but are in no way limited to, methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl,neopentyl, hexyl, allyl, but-2-enyl, but-3-enyl, and the like. In someembodiments, an alkyl is a C₁-C₆alkyl.

The term “alkylene” refers to a divalent alkyl radical. Any of the abovementioned monovalent alkyl groups may be an alkylene by abstraction of asecond hydrogen atom from the alkyl. In one aspect, an alkelene is aC₁-C₁₀alkylene. In another aspect, an alkylene is a C₁-C₆alkylene.Typical alkylene groups include, but are not limited to, —CH₂—,—CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH(CH₃)—, —CH₂C(CH₃)₂—, —CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂CH₂—, and the like.

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as definedherein.

The term “alkylamine” refers to the —N(alkyl)_(x)H_(y) group, where xand y are selected from the group x=1, y=1 and x=2, y=0.

The term “aromatic” refers to a planar ring having a delocalizedπ-electron system containing 4n+2π electrons, where n is an integer.Aromatic rings can be formed from five, six, seven, eight, nine, ten, ormore than ten atoms. Aromatics are optionally substituted. The term“aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl) andheterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g.,pyridine). The term includes monocyclic or fused-ring polycyclic (i.e.,rings which share adjacent pairs of carbon atoms) groups.

The term “carbocyclic” or “carbocycle” refers to a ring or ring systemwhere the atoms forming the backbone of the ring are all carbon atoms.The term thus distinguishes carbocyclic from heterocyclic rings in whichthe ring backbone contains at least one atom which is different fromcarbon.

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. Aryl rings are formed byfive, six, seven, eight, nine, or more than nine carbon atoms. Arylgroups are optionally substituted. In one aspect, an aryl is a phenyl ora naphthalenyl. In one aspect, an aryl is a phenyl. In one aspect, anaryl is a C₆-C₁₀aryl. Depending on the structure, an aryl group can be amonoradical or a diradical (i.e., an arylene group). Exemplary arylenesinclude, but are not limited to, phenyl-1,2-ene, phenyl-1,3-ene, andphenyl-1,4-ene.

The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic,non-aromatic radical, wherein each of the atoms forming the ring (i.e.skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, orpartially unsaturated. Cycloalkyls may be fused with an aromatic ring,and the point of attachment is at a carbon that is not an aromatic ringcarbon atom. Cycloalkyl groups include groups having from 3 to 10 ringatoms. In some embodiments, cycloalkyl groups are selected from amongcyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups may besubstituted or unsubstituted. Depending on the structure, a cycloalkylgroup can be a monoradical or a diradical (i.e., an cycloalkylene group,such as, but not limited to, cyclopropan-1,1-diyl, cyclobutan-1,1-diyl,cyclopentan-1,1-diyl, cyclohexan-1,1-diyl, cyclohexan-1,4-diyl,cycloheptan-1,1-diyl, and the like). In one aspect, a cycloalkyl is aC₃-C₆cycloalkyl.

The term “halo” or, alternatively, “halogen” or “halide” means fluoro,chloro, bromo or iodo.

The term “haloalkyl” refers to an alkyl group in which one or morehydrogen atoms are replaced by one or more halide atoms. In one aspect,a haloalkyl is a C₁-C₆haloalkyl.

The term “haloalkylene” refers to an alkylene group in which one or morehydrogen atoms are replaced by one or more halide atoms. In one aspect,a haloalkylene is a C₁-C₆haloalkylene.

The term “fluoroalkyl” refers to an alkyl in which one or more hydrogenatoms are replaced by a fluorine atom. In one aspect, a fluoralkyl is aC₁-C₆fluoroalkyl.

The term “fluoroalkylene” refers to an alkylene in which one or morehydrogen atoms are replaced by a fluorine atom. In one aspect, afluoralkylene is a C₁-C₆fluoroalkylene.

The term “heteroalkyl” refers to an alkyl group in which one or moreskeletal atoms of the alkyl are selected from an atom other than carbon,e.g., oxygen, nitrogen (e.g. —NH—, —N(alkyl)-, sulfur, or combinationsthereof. In one aspect, a heteroalkyl is a C₁-C₆heteroalkyl.

The term “heteroalkylene” refers to an alkylene group in which one ormore skeletal atoms of the alkyl are selected from an atom other thancarbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinationsthereof. In one aspect, a heteroalkylene is a C₁-C₆heteroalkylene.Exemplary heteroalkylenes include, but are not limited to, —OCH₂—,—OCH(CH₃)—, —OC(CH₃)₂—, —OCH₂CH₂—, —OCH₂CH₂CH₂—, —CH₂O—, —CH(CH₃)O—,—C(CH₃)₂O—, —CH₂CH₂O—, —CH₂OCH₂—, —CH₂OCH₂CH₂—, —CH₂CH₂OCH₂—, —SCH₂—,—SCH(CH₃)—, —SC(CH₃)₂—, —SCH₂CH₂—, —CH₂S—, —CH(CH₂)S—, —C(CH₃)₂S—,—CH₂CH₂S—, —CH₂SCH₂—, —CH₂SCH₂CH₂—, —CH₂CH₂SCH₂—, —SO₂CH₂—,—SO₂CH(CH₃)—, —SO₂C(CH₃)₂—, —SO₂CH₂CH₂—, —CH₂SO₂—, —CH(CH₃)SO₂—,—C(CH₃)₂SO₂—, —CH₂CH₂SO₂—, —CH₂SO₂CH₂—, —CH₂SO₂CH₂CH₂—, —CH₂CH₂SO₂CH₂—,—NHCH₂—, —NHCH(CH₃)—, —NHC(CH₃)₂—, —NHCH₂CH₂—, —CH₂NH—, —CH(CH₃)NH—,—C(CH₃)₂NH—, —CH₂CH₂NH—, —CH₂NHCH₂—, —CH₂NHCH₂CH₂—, —CH₂CH₂NHCH₂—, andthe like.

The term “heterocycle” or “heterocyclic” refers to heteroaromatic rings(also known as heteroaryls) and heterocycloalkyl rings (also known asheteroalicyclic groups) containing one to four heteroatoms in thering(s), where each heteroatom in the ring(s) is selected from O, S andN, wherein each heterocyclic group has from 4 to 10 atoms in its ringsystem, and with the proviso that the any ring does not contain twoadjacent O or S atoms. Non-aromatic heterocyclic groups (also known asheterocycloalkyls) include groups having only 3 atoms in their ringsystem, but aromatic heterocyclic groups must have at least 5 atoms intheir ring system. The heterocyclic groups include benzo-fused ringsystems. An example of a 3-membered heterocyclic group is aziridinyl. Anexample of a 4-membered heterocyclic group is azetidinyl. An example ofa 5-membered heterocyclic group is thiazolyl. An example of a 6-memberedheterocyclic group is pyridyl, and an example of a 10-memberedheterocyclic group is quinolinyl. Examples of non-aromatic heterocyclicgroups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups may be C-attached (or C-linked) orN-attached where such is possible. For instance, a group derived frompyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).Further, a group derived from imidazole may be imidazol-1-yl orimidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl orimidazol-5-yl (all C-attached). The heterocyclic groups includebenzo-fused ring systems. Non-aromatic heterocycles may be substitutedwith one or two oxo (═O) moieties, such as pyrrolidin-2-one.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groupsinclude the following moieties:

and the like. Monocyclic heteroaryls include pyridinyl, imidazolyl,pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl,thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Insome embodiments, a heteroaryl contains 0-3 N atoms in the ring. In someembodiments, a heteroaryl contains 1-3 N atoms in the ring. In someembodiments, a heteroaryl contains 0-3 N atoms, 0-1 O atoms, and 0-1 Satoms in the ring. In some embodiments, a heteroaryl is a monocyclic orbicyclic heteroaryl. In some embodiments, heteroaryl is aC₁-C₉heteroaryl. In some embodiments, monocyclic heteroaryl is aC₁-C₅heteroaryl. In some embodiments, monocyclic heteroaryl is a5-membered or 6-membered heteroaryl. In some embodiments, bicyclicheteroaryl is a C₆-C₉heteroaryl. Depending on the structure, aheteroaryl group can be a monoradical or a diradical (i.e., aheteroarylene group).

A “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkylgroup that includes at least one heteroatom selected from nitrogen,oxygen and sulfur. The radicals may be fused with an aryl or heteroaryl.Illustrative examples of heterocycloalkyl groups, also referred to asnon-aromatic heterocycles, include:

and the like. In some embodiments, the heterocycloalkyl is selected fromoxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, and indolinyl. In some embodiments, theheterocycloalkyl is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,thiomorpholinyl, or piperazinyl. The term heteroalicyclic also includesall ring forms of the carbohydrates, including but not limited to themonosaccharides, the disaccharides and the oligosaccharides. In oneaspect, a heterocycloalkyl is a C₂-C₁₀heterocycloalkyl. In anotheraspect, a heterocycloalkyl is a C₄-C₁₀heterocycloalkyl. In someembodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. Insome embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atomsand 0-1 S atoms in the ring.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure. In one aspect, when a group describedherein is a bond, the referenced group is absent thereby allowing a bondto be formed between the remaining identified groups.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

As used herein, “carboxylic acid bioisostere” refers to a functionalgroup or moiety that exhibits similar physical, biological and/orchemical properties as a carboxylic acid moiety. Examples of carboxylicacid bioisosteres include, but are not limited to,

and the like.

The term “optionally substituted” or “substituted” means that thereferenced group may be substituted with one or more additional group(s)individually and independently selected from alkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone,cyano, halo, nitro, haloalkyl, fluoroalkyl, fluoroalkoxy, and amino,including mono- and di-substituted amino groups, and the protectedderivatives thereof. By way of example optional substituents areindependently selected from halide, —CN, —NO₂, and -LR, wherein each Lis independently selected from a bond, —O—, —C(═O)—, —C(═O)O—, —S—,—S(═O)—, —S(═O)₂—, —NH—, —NHC(═O)—, —C(═O)NH—, S(═O)₂NH—, —NHS(═O)₂,—OC(═O)NH—, —NHC(═O)O—, or —(C₁-C₆alkylene)-; and each R is selectedfrom H, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl,or heterocycloalkyl. In some embodiments, optional substituents areindependently selected from halogen, —CN, —NH₂, —NH(CH₃), —N(CH₃)₂, —OH,alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide,arylsulfoxide, alkylsulfone, and arylsulfone. In some embodiments,optional substituents are independently selected from halogen, —CN,—NH₂, —NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)alkyl, —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl),—S(═O)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy,fluoroalkoxy, —S-alkyl, or —S(═O)₂alkyl. In some embodiments, optionalsubstituents are independently selected from halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)alkyl, —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl,heteroalkyl, alkoxy, and fluoroalkoxy. In some embodiments, optionalsubstituents are independently selected from halogen, —CN, —NH₂, —OH,—NH(CH₃), —N(CH₃)₂, —CH₃, —CH₂CH₃, —CF₃, —CH₂CF₃, —OCH₃, —OCH₂CH₃, and—OCF₃. In some embodiments, substituted groups are substituted with oneor two of the preceding groups. In some embodiments, an optionalsubstituent on an aliphatic carbon atom (acyclic or cyclic, saturated orunsaturated carbon atoms, excluding aromatic carbon atoms) includes oxo(═O).

In certain embodiments, the compounds presented herein possess one ormore stereocenters and each center independently exists in either the Ror S configuration. The compounds presented herein include alldiastereomeric, enantiomeric, and epimeric forms as well as theappropriate mixtures thereof. Stereoisomers are obtained, if desired, bymethods such as, stereoselective synthesis and/or the separation ofstereoisomers by chiral chromatographic columns.

The methods and formulations described herein include the use ofN-oxides (if appropriate), crystalline forms (also known as polymorphs),or pharmaceutically acceptable salts of compounds having the structureof Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII),(VIIIa), (IX), (IXa) or (X), as well as active metabolites of thesecompounds having the same type of activity. In some situations,compounds may exist as tautomers. All tautomers are included within thescope of the compounds presented herein. In specific embodiments, thecompounds described herein exist in solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. In otherembodiments, the compounds described herein exist in unsolvated form.

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

The term “modulate” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

The term “modulator” as used herein, refers to a molecule that interactswith a target either directly or indirectly. The interactions include,but are not limited to, the interactions of an agonist, partial agonist,an inverse agonist, antagonist, degrader, AR trafficking modulator, ARDNA-binding inhibitor. In some embodiments, a modulator is anantagonist. In some embodiments, a modulator is an inverse agonist,antagonist, degrader, AR trafficking modulator and/or a DNA bindinginhibitor.

The term “antagonist” as used herein, refers to a small-molecule agentthat binds to a nuclear hormone receptor and subsequently decreases theagonist induced transcriptional activity of the nuclear hormonereceptor.

The term “agonist” as used herein, refers to a small-molecule agent thatbinds to a nuclear hormone receptor and subsequently increases nuclearhormone receptor transcriptional activity in the absence of a knownagonist.

The term “inverse agonist” as used herein, refers to a small-moleculeagent that binds to a nuclear hormone receptor and subsequentlydecreases the basal level of nuclear hormone receptor transcriptionalactivity that is present in the absence of a known agonist.

The term “degrader” as used herein, refers to a small molecule agentthat binds to a nuclear hormone receptor and subsequently lowers thesteady state protein levels of said receptor.

The term “AR trafficking modulator” as used herein, refers to asmall-molecule agent that binds to a nuclear hormone receptor andsubsequently alters the normal subcellular location of the receptorthereby interfering with its function and signaling.

The term “DNA-binding inhibitor” as used herein, refers to asmall-molecule agent that binds to a nuclear hormone receptor andsubsequently prevents DNA binding of the receptor thereby interferingwith its function and signaling.

The term “AR-dependent”, as used herein, refers to diseases orconditions that would not occur, or would not occur to the same extent,in the absence of androgen receptors.

The term “AR-mediated”, as used herein, refers to diseases or conditionsthat might occur in the absence of androgen receptors but can occur inthe presence of androgen receptors.

“Selective” with respect to androgen receptors means that the compoundpreferentially binds to androgen receptors versus other nuclearreceptors. In some embodiments, a selective androgen receptor modulatorpreferentially binds to androgen receptors and displays little, if any,affinity to other nuclear receptors.

The term “cancer” as used herein refers to an abnormal growth of cellswhich tend to proliferate in an uncontrolled way and, in some cases, tometastasize (spread).

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result can bereduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case may be determinedusing techniques, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of Formula (I), (Ia), (II), (III), (IV),(V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) and a co-agent,are both administered to a patient simultaneously in the form of asingle entity or dosage. The term “non-fixed combination” means that theactive ingredients, e.g. a compound of Formula (I), (Ia), (II), (III),(IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) and aco-agent, are administered to a patient as separate entities eithersimultaneously, concurrently or sequentially with no specificintervening time limits, wherein such administration provides effectivelevels of the two compounds in the body of the patient. The latter alsoapplies to cocktail therapy, e.g. the administration of three or moreactive ingredients.

The terms “kit” and “article of manufacture” are used as synonyms.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes) by which a particular substance is changed by anorganism. Thus, enzymes may produce specific structural alterations to acompound. For example, cytochrome P450 catalyzes a variety of oxidativeand reductive reactions while uridine diphosphate glucuronyltransferasescatalyze the transfer of an activated glucuronic-acid molecule toaromatic alcohols, aliphatic alcohols, carboxylic acids, amines and freesulphydryl groups. Metabolites of the compounds disclosed herein areoptionally identified either by administration of compounds to a hostand analysis of tissue samples from the host, or by incubation ofcompounds with hepatic cells in vitro and analysis of the resultingcompounds.

The term “subject” or “patient” encompasses mammals. Examples of mammalsinclude, but are not limited to, any member of the Mammalian class:humans, non-human primates such as chimpanzees, and other apes andmonkey species; farm animals such as cattle, horses, sheep, goats,swine; domestic animals such as rabbits, dogs, and cats; laboratoryanimals including rodents, such as rats, mice and guinea pigs, and thelike. In one embodiment, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating at least one symptom of a diseasedisease or condition, preventing additional symptoms, inhibiting thedisease or condition, e.g., arresting the development of the disease orcondition, relieving the disease or condition, causing regression of thedisease or condition, relieving a condition caused by the disease orcondition, or stopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

Routes of Administration

Suitable routes of administration include, but are not limited to, oral,intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary,transmucosal, transdermal, vaginal, otic, nasal, and topicaladministration. In addition, by way of example only, parenteral deliveryincludes intramuscular, subcutaneous, intravenous, intramedullaryinjections, as well as intrathecal, direct intraventricular,intraperitoneal, intralymphatic, and intranasal injections.

In certain embodiments, a compound as described herein is administeredin a local rather than systemic manner, for example, via injection ofthe compound directly into an organ, often in a depot preparation orsustained release formulation. In specific embodiments, long actingformulations are administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection.Furthermore, in other embodiments, the drug is delivered in a targeteddrug delivery system, for example, in a liposome coated withorgan-specific antibody. In such embodiments, the liposomes are targetedto and taken up selectively by the organ. In yet other embodiments, thecompound as described herein is provided in the form of a rapid releaseformulation, in the form of an extended release formulation, or in theform of an intermediate release formulation. In yet other embodiments,the compound described herein is administered topically.

Pharmaceutical Compositions/Formulations

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. Pharmaceutical compositions are formulatedin a conventional manner using one or more pharmaceutically acceptableinactive ingredients that facilitate processing of the active compoundsinto preparations that can be used pharmaceutically. Proper formulationis dependent upon the route of administration chosen. A summary ofpharmaceutical compositions described herein can be found, for example,in Remington: The Science and Practice of Pharmacy, Nineteenth Ed(Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins 1999), herein incorporated by reference for such disclosure.

Provided herein are pharmaceutical compositions that include a compoundof Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII),(VIIIa), (IX), (IXa) or (X) and at least one pharmaceutically acceptableinactive ingredient. In some embodiments, the compounds described hereinare administered as pharmaceutical compositions in which a compound ofFormula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa),(IX), (IXa) or (X) is mixed with other active ingredients, as incombination therapy. In other embodiments, the pharmaceuticalcompositions include other medicinal or pharmaceutical agents, carriers,adjuvants, preserving, stabilizing, wetting or emulsifying agents,solution promoters, salts for regulating the osmotic pressure, and/orbuffers. In yet other embodiments, the pharmaceutical compositionsinclude other therapeutically valuable substances.

A pharmaceutical composition, as used herein, refers to a mixture of acompound of Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII),(VIII), (VIIIa), (IX), (IXa) or (X) with other chemical components (i.e.pharmaceutically acceptable inactive ingredients), such as carriers,excipients, binders, filling agents, suspending agents, flavoringagents, sweetening agents, disintegrating agents, dispersing agents,surfactants, lubricants, colorants, diluents, solubilizers, moisteningagents, plasticizers, stabilizers, penetration enhancers, wettingagents, anti-foaming agents, antioxidants, preservatives, or one or morecombination thereof. The pharmaceutical composition facilitatesadministration of the compound to a mammal.

A therapeutically effective amount can vary widely depending on theseverity of the disease, the age and relative health of the subject, thepotency of the compound used and other factors. The compounds can beused singly or in combination with one or more therapeutic agents ascomponents of mixtures.

The pharmaceutical formulations described herein are administered to asubject by appropriate administration routes, including but not limitedto, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular),intranasal, buccal, topical, rectal, or transdermal administrationroutes. The pharmaceutical formulations described herein include, butare not limited to, aqueous liquid dispersions, self-emulsifyingdispersions, solid solutions, liposomal dispersions, aerosols, soliddosage forms, powders, immediate release formulations, controlledrelease formulations, fast melt formulations, tablets, capsules, pills,delayed release formulations, extended release formulations, pulsatilerelease formulations, multiparticulate formulations, and mixed immediateand controlled release formulations.

Pharmaceutical compositions including a compound of Formula (I), (Ia),(II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X)are manufactured in a conventional manner, such as, by way of exampleonly, by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping orcompression processes.

The pharmaceutical compositions will include at least one compound ofFormula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa),(IX), (IXa) or (X) as an active ingredient in free-acid or free-baseform, or in a pharmaceutically acceptable salt form. In addition, themethods and pharmaceutical compositions described herein include the useof N-oxides (if appropriate), crystalline forms, amorphous phases, aswell as active metabolites of these compounds having the same type ofactivity. In some embodiments, compounds described herein exist inunsolvated form or in solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.

The pharmaceutical compositions described herein, which include acompound of Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII),(VIII), (VIIIa), (IX), (IXa) or (X) are formulated into any suitabledosage form, including but not limited to, aqueous oral dispersions,liquids, gels, syrups, elixirs, slurries, suspensions, solid oral dosageforms, controlled release formulations, fast melt formulations,effervescent formulations, lyophilized formulations, tablets, powders,pills, dragees, capsules, delayed release formulations, extended releaseformulations, pulsatile release formulations, multiparticulateformulations, and mixed immediate release and controlled releaseformulations.

Pharmaceutical preparations that are administered orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules contain the active ingredients in admixture with filler such aslactose, binders such as starches, and/or lubricants such as talc ormagnesium stearate and, optionally, stabilizers. In some embodiments,the push-fit capsules do not include any other ingredient besides thecapsule shell and the active ingredient. In soft capsules, the activecompounds are dissolved or suspended in suitable liquids, such as fattyoils, liquid paraffin, or liquid polyethylene glycols. In someembodiments, stabilizers are added.

All formulations for oral administration are in dosages suitable forsuch administration.

In one aspect, solid oral dosage forms are prepared by mixing a compoundof Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII),(VIIIa), (IX), (IXa) or (X) with one or more of the following:antioxidants, flavoring agents, and carrier materials such as binders,suspending agents, disintegration agents, filling agents, surfactants,solubilizers, stabilizers, lubricants, wetting agents, and diluents.

In some embodiments, the solid dosage forms disclosed herein are in theform of a tablet, (including a suspension tablet, a fast-melt tablet, abite-disintegration tablet, a rapid-disintegration tablet, aneffervescent tablet, or a caplet), a pill, a powder, a capsule, soliddispersion, solid solution, bioerodible dosage form, controlled releaseformulations, pulsatile release dosage forms, multiparticulate dosageforms, beads, pellets, granules. In other embodiments, thepharmaceutical formulation is in the form of a powder. In still otherembodiments, the pharmaceutical formulation is in the form of a tablet.In other embodiments, pharmaceutical formulations of the compound ofFormula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa),(IX), (IXa) or (X) is in the form of a capsule.

In some embodiments, solid dosage forms, e.g., tablets, effervescenttablets, and capsules, are prepared by mixing particles of a compound ofFormula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa),(IX), (IXa) or (X) with one or more pharmaceutical excipients to form abulk blend composition. The bulk blend is readily subdivided intoequally effective unit dosage forms, such as tablets, pills, andcapsules. In some embodiments, the individual unit dosages include filmcoatings. These formulations are manufactured by conventionalformulation techniques.

Conventional formulation techniques include, e.g., one or a combinationof methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dryor non-aqueous granulation, (5) wet granulation, or (6) fusion. Othermethods include, e.g., spray drying, pan coating, melt granulation,granulation, fluidized bed spray drying or coating (e.g., wurstercoating), tangential coating, top spraying, tableting, extruding and thelike.

In some embodiments, tablets will include a film surrounding the finalcompressed tablet. In some embodiments, the film coating can provide adelayed release of the compound of Formula (I), (Ia), (II), (III), (IV),(V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) from theformulation. In other embodiments, the film coating aids in patientcompliance (e.g., Opadry® coatings or sugar coating). Film coatingsincluding Opadry® typically range from about 1% to about 3% of thetablet weight.

A capsule may be prepared, for example, by placing the bulk blend of theformulation of the compound described above, inside of a capsule. Insome embodiments, the formulations (non-aqueous suspensions andsolutions) are placed in a soft gelatin capsule. In other embodiments,the formulations are placed in standard gelatin capsules or non-gelatincapsules such as capsules comprising HPMC. In other embodiments, theformulation is placed in a sprinkle capsule, wherein the capsule isswallowed whole or the capsule is opened and the contents sprinkled onfood prior to eating.

In various embodiments, the particles of the compound of Formula (I),(Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa)or (X) and one or more excipients are dry blended and compressed into amass, such as a tablet, having a hardness sufficient to provide apharmaceutical composition that substantially disintegrates within lessthan about 30 minutes, less than about 35 minutes, less than about 40minutes, less than about 45 minutes, less than about 50 minutes, lessthan about 55 minutes, or less than about 60 minutes, after oraladministration, thereby releasing the formulation into thegastrointestinal fluid.

In other embodiments, a powder including a compound of Formula (I),(Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa)or (X) is formulated to include one or more pharmaceutical excipientsand flavors. Such a powder is prepared, for example, by mixing the thecompound of Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII),(VIII), (VIIIa), (IX), (IXa) or (X) and optional pharmaceuticalexcipients to form a bulk blend composition. Additional embodiments alsoinclude a suspending agent and/or a wetting agent. This bulk blend isuniformly subdivided into unit dosage packaging or multi-dosagepackaging units.

In still other embodiments, effervescent powders are also prepared.Effervescent salts have been used to disperse medicines in water fororal administration.

In some embodiments, the pharmaceutical solid oral dosage forms areformulated to provide a controlled release of the compound of Formula(I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX),(IXa) or (X). Controlled release refers to the release of the compoundof Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII),(VIIIa), (IX), (IXa) or (X) from a dosage form in which it isincorporated according to a desired profile over an extended period oftime. Controlled release profiles include, for example, sustainedrelease, prolonged release, pulsatile release, and delayed releaseprofiles. In contrast to immediate release compositions, controlledrelease compositions allow delivery of an agent to a subject over anextended period of time according to a predetermined profile. Suchrelease rates can provide therapeutically effective levels of agent foran extended period of time and thereby provide a longer period ofpharmacologic response while minimizing side effects as compared toconventional rapid release dosage forms. Such longer periods of responseprovide for many inherent benefits that are not achieved with thecorresponding short acting, immediate release preparations.

In some embodiments, the solid dosage forms described herein areformulated as enteric coated delayed release oral dosage forms, i.e., asan oral dosage form of a pharmaceutical composition as described hereinwhich utilizes an enteric coating to affect release in the smallintestine or large intestine. In one aspect, the enteric coated dosageform is a compressed or molded or extruded tablet/mold (coated oruncoated) containing granules, powder, pellets, beads or particles ofthe active ingredient and/or other composition components, which arethemselves coated or uncoated. In one aspect, the enteric coated oraldosage form is in the form of a capsule containing pellets, beads orgranules, which include a compound of Formula (I), (Ia), (II), (III),(IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) that arecoated or uncoated.

Conventional coating techniques such as spray or pan coating areemployed to apply coatings. The coating thickness must be sufficient toensure that the oral dosage form remains intact until the desired siteof topical delivery in the intestinal tract is reached.

In other embodiments, the formulations described herein are deliveredusing a pulsatile dosage form. A pulsatile dosage form is capable ofproviding one or more immediate release pulses at predetermined timepoints after a controlled lag time or at specific sites. Exemplarypulsatile dosage forms and methods of their manufacture are disclosed inU.S. Pat. Nos. 5,011,692, 5,017,381, 5,229,135, 5,840,329 and 5,837,284.In one embodiment, the pulsatile dosage form includes at least twogroups of particles, (i.e. multiparticulate) each containing theformulation described herein. The first group of particles provides asubstantially immediate dose of the compound of Formula (I), (Ia), (II),(III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) uponingestion by a mammal. The first group of particles can be eitheruncoated or include a coating and/or sealant. In one aspect, the secondgroup of particles comprises coated particles. The coating on the secondgroup of particles provides a delay of from about 2 hours to about 7hours following ingestion before release of the second dose. Suitablecoatings for pharmaceutical compositions are described herein or knownin the art.

In some embodiments, pharmaceutical formulations are provided thatinclude particles of a compound of Formula (I), (Ia), (II), (III), (IV),(V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) and at least onedispersing agent or suspending agent for oral administration to asubject. The formulations may be a powder and/or granules forsuspension, and upon admixture with water, a substantially uniformsuspension is obtained.

In one aspect, liquid formulation dosage forms for oral administrationare in the form of aqueous suspensions selected from the groupincluding, but not limited to, pharmaceutically acceptable aqueous oraldispersions, emulsions, solutions, elixirs, gels, and syrups. See, e.g.,Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp.754-757 (2002). In addition to the particles of the compound of Formula(I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX),(IXa) or (X), the liquid dosage forms include additives, such as: (a)disintegrating agents; (b) dispersing agents; (c) wetting agents; (d) atleast one preservative, (e) viscosity enhancing agents, (f) at least onesweetening agent, and (g) at least one flavoring agent. In someembodiments, the aqueous dispersions can further include a crystallineinhibitor.

Buccal formulations that include a compound of Formula (I), (Ia), (II),(III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) areadministered using a variety of formulations known in the art. Forexample, such formulations include, but are not limited to, U.S. Pat.Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739,136. In addition, thebuccal dosage forms described herein can further include a bioerodible(hydrolysable) polymeric carrier that also serves to adhere the dosageform to the buccal mucosa. For buccal or sublingual administration, thecompositions may take the form of tablets, lozenges, or gels formulatedin a conventional manner.

In some embodiments, compounds of Formula (I), (Ia), (II), (III), (IV),(V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) are prepared astransdermal dosage forms. In one embodiments, the transdermalformulations described herein include at least three components: (1) aformulation of a compound of Formula (I), (Ia), (II), (III), (IV), (V),(VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X); (2) a penetrationenhancer; and (3) an aqueous adjuvant. In some embodiments thetransdermal formulations include additional components such as, but notlimited to, gelling agents, creams and ointment bases, and the like. Insome embodiments, the transdermal formulation further include a woven ornon-woven backing material to enhance absorption and prevent the removalof the transdermal formulation from the skin. In other embodiments, thetransdermal formulations described herein can maintain a saturated orsupersaturated state to promote diffusion into the skin.

In one aspect, formulations suitable for transdermal administration ofcompounds described herein employ transdermal delivery devices andtransdermal delivery patches and can be lipophilic emulsions orbuffered, aqueous solutions, dissolved and/or dispersed in a polymer oran adhesive. In one aspect, such patches are constructed for continuous,pulsatile, or on demand delivery of pharmaceutical agents. Stillfurther, transdermal delivery of the compounds described herein can beaccomplished by means of iontophoretic patches and the like. In oneaspect, transdermal patches provide controlled delivery of the compoundof Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII),(VIIIa), (IX), (IXa) or (X). In one aspect, transdermal devices are inthe form of a bandage comprising a backing member, a reservoircontaining the compound optionally with carriers, optionally a ratecontrolling barrier to deliver the compound to the skin of the host at acontrolled and predetermined rate over a prolonged period of time, andmeans to secure the device to the skin.

In one aspect, a compound of Formula (I), (Ia), (II), (III), (IV), (V),(VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) is formulated into apharmaceutical composition suitable for intramuscular, subcutaneous, orintravenous injection. In one aspect, formulations suitable forintramuscular, subcutaneous, or intravenous injection includephysiologically acceptable sterile aqueous or non-aqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and non-aqueous carriers, diluents,solvents, or vehicles include water, ethanol, polyols (propyleneglycol,polyethylene-glycol, glycerol, cremophor and the like), suitablemixtures thereof, vegetable oils (such as olive oil) and injectableorganic esters such as ethyl oleate. Proper fluidity can be maintained,for example, by the use of a coating such as lecithin, by themaintenance of the required particle size in the case of dispersions,and by the use of surfactants. In some embodiments, formulationssuitable for subcutaneous injection also contain additives such aspreserving, wetting, emulsifying, and dispensing agents. Prevention ofthe growth of microorganisms can be ensured by various antibacterial andantifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid,and the like. In some cases it is desirable to include isotonic agents,such as sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, such as aluminum monostearate and gelatin.

For intravenous injections, compounds described herein are formulated inaqueous solutions, preferably in physiologically compatible buffers suchas Hank's solution, Ringer's solution, or physiological saline buffer.For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants aregenerally known in the art. For other parenteral injections, appropriateformulations include aqueous or nonaqueous solutions, preferably withphysiologically compatible buffers or excipients. Such excipients areknown.

Parenteral injections may involve bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multi-dose containers, with an addedpreservative. The pharmaceutical composition described herein may be ina form suitable for parenteral injection as a sterile suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. In one aspect, the active ingredient is in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

In certain embodiments, delivery systems for pharmaceutical compoundsmay be employed, such as, for example, liposomes and emulsions. Incertain embodiments, compositions provided herein can also include anmucoadhesive polymer, selected from among, for example,carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

In some embodiments, the compounds described herein may be administeredtopically and can be formulated into a variety of topicallyadministrable compositions, such as solutions, suspensions, lotions,gels, pastes, medicated sticks, balms, creams or ointments. Suchpharmaceutical compounds can contain solubilizers, stabilizers, tonicityenhancing agents, buffers and preservatives.

Methods of Dosing and Treatment Regimens

In one embodiment, the compounds of Formula (I), (Ia), (II), (III),(IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) and (X) are used inthe preparation of medicaments for the treatment of diseases orconditions in a mammal that would benefit from a reduction of androgenreceptor activity. Methods for treating any of the diseases orconditions described herein in a mammal in need of such treatment,involves administration of pharmaceutical compositions that include atleast one compound of Formula (I), (Ia), (II), (III), (IV), (V), (VI),(VII), (VIII), (VIIIa), (IX), (IXa) or (X) or a pharmaceuticallyacceptable salt, active metabolite, prodrug, or pharmaceuticallyacceptable solvate thereof, in therapeutically effective amounts to saidsubject.

In certain embodiments, the compositions containing the compound(s)described herein are administered for prophylactic and/or therapeutictreatments. In certain therapeutic applications, the compositions areadministered to a patient already suffering from a disease or condition,in an amount sufficient to cure or at least partially arrest at leastone of the symptoms of the disease or condition. Amounts effective forthis use depend on the severity and course of the disease or condition,previous therapy, the patient's health status, weight, and response tothe drugs, and the judgment of the treating physician. Therapeuticallyeffective amounts are optionally determined by methods including, butnot limited to, a dose escalation clinical trial.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in a patient, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician. In one aspect, prophylactic treatments include administeringto a mammal, who previously experienced at least one symtom of thedisease being treated and is currently in remission, a pharmaceuticalcomposition comprising a compound of Formula (I), (Ia), (II), (III),(IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) in order toprevent a return of the symptoms of the disease or condition.

In certain embodiments wherein the patient's condition does not improve,upon the doctor's discretion the administration of the compounds areadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In certain embodiments wherein a patient's status does improve, the doseof drug being administered may be temporarily reduced or temporarilysuspended for a certain length of time (i.e., a “drug holiday”). Inspecific embodiments, the length of the drug holiday is between 2 daysand 1 year, including by way of example only, 2 days, 3 days, 4 days, 5days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, ormore than 28 days. The dose reduction during a drug holiday is, by wayof example only, by 10%400%, including by way of example only 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, and 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, in specificembodiments, the dosage or the frequency of administration, or both, isreduced, as a function of the symptoms, to a level at which the improveddisease, disorder or condition is retained. In certain embodiments,however, the patient requires intermittent treatment on a long-termbasis upon any recurrence of symptoms.

The amount of a given agent that corresponds to such an amount variesdepending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight, sex) of thesubject or host in need of treatment, but can nevertheless be determinedaccording to the particular circumstances surrounding the case,including, e.g., the specific agent being administered, the route ofadministration, the condition being treated, and the subject or hostbeing treated.

In general, however, doses employed for adult human treatment aretypically in the range of 0.01 mg-5000 mg per day. In one aspect, dosesemployed for adult human treatment are from about 1 mg to about 1000 mgper day. In one embodiment, the desired dose is conveniently presentedin a single dose or in divided doses administered simultaneously (orover a short period of time) or at appropriate intervals, for example astwo, three, four or more sub-doses per day.

In one embodiment, the daily dosages appropriate for the compound ofFormula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa),(IX), (IXa) or (X) described herein are from about 0.01 to about 10mg/kg per body weight. In specific embodiments, an indicated dailydosage in a large mammal, including, but not limited to, humans, is inthe range from about 0.5 mg to about 1000 mg, conveniently administeredin divided doses, including, but not limited to, up to four times a day.In one embodiment, the daily dosage is administered in extended releaseform. In certain embodiments, suitable unit dosage forms for oraladministration comprise from about 1 to 500 mg active ingredient. Inother embodiments, the daily dosage or the amount of active in thedosage form are lower or higher than the ranges indicated herein, basedon a number of variables in regard to an individual treatment regime. Invarious embodiments, the daily and unit dosages are altered depending ona number of variables including, but not limited to, the activity of thecompound used, the disease or condition to be treated, the mode ofadministration, the requirements of the individual subject, the severityof the disease or condition being treated, and the judgment of thepractitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens aredetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ and the ED₅₀. The dose ratio between the toxic andtherapeutic effects is the therapeutic index and it is expressed as theratio between LD₅₀ and ED₅₀. In certain embodiments, the data obtainedfrom cell culture assays and animal studies are used in formulating thetherapeutically effective daily dosage range and/or the therapeuticallyeffective unit dosage amount for use in mammals, including humans. Insome embodiments, the daily dosage amount of the compounds describedherein lies within a range of circulating concentrations that includethe ED₅₀ with minimal toxicity. In certain embodiments, the daily dosagerange and/or the unit dosage amount varies within this range dependingupon the dosage form employed and the route of administration utilized.

Combination Treatments

In certain instances, it is appropriate to administer at least onecompound of Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII),(VIII), (VIIIa), (IX), (IXa) or (X) in combination with anothertherapeutic agent.

In one embodiment, the therapeutic effectiveness of one of the compoundsdescribed herein is enhanced by administration of an adjuvant (i.e., byitself the adjuvant may have minimal therapeutic benefit, but incombination with another therapeutic agent, the overall therapeuticbenefit to the patient is enhanced). Or, in some embodiments, thebenefit experienced by a patient is increased by administering one ofthe compounds described herein with another therapeutic agent (whichalso includes a therapeutic regimen) that also has therapeutic benefit.

In one specific embodiment, a compound of Formula (I), (Ia), (II),(III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) isco-administered with a second therapeutic agent, wherein the compound ofFormula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa),(IX), (IXa) or (X) and the second therapeutic agent modulate differentaspects of the disease, disorder or condition being treated, therebyproviding a greater overall benefit than administration of eithertherapeutic agent alone.

In any case, regardless of the disease, disorder or condition beingtreated, the overall benefit experienced by the patient may simply beadditive of the two therapeutic agents or the patient may experience asynergistic benefit.

In certain embodiments, different therapeutically-effective dosages ofthe compounds disclosed herein will be utilized in formulatingpharmaceutical composition and/or in treatment regimens when thecompounds disclosed herein are administered in combination with one ormore additional agent, such as an additional therapeutically effectivedrug, an adjuvant or the like. Therapeutically-effective dosages ofdrugs and other agents for use in combination treatment regimens can bedetermined by means similar to those set forth hereinabove for theactives themselves. Furthermore, the methods of prevention/treatmentdescribed herein encompasses the use of metronomic dosing, i.e.,providing more frequent, lower doses in order to minimize toxic sideeffects. In some embodiments, a combination treatment regimenencompasses treatment regimens in which administration of a compound ofFormula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa),(IX), (IXa) or (X) is initiated prior to, during, or after treatmentwith a second agent described herein, and continues until any timeduring treatment with the second agent or after termination of treatmentwith the second agent. It also includes treatments in which a compoundof Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII),(VIIIa), (IX), (IXa) or (X) and the second agent being used incombination are administered simultaneously or at different times and/orat decreasing or increasing intervals during the treatment period.Combination treatment further includes periodic treatments that startand stop at various times to assist with the clinical management of thepatient.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, is modified inaccordance with a variety of factors. These factors include the disease,disorder or condition from which the subject suffers, as well as theage, weight, sex, diet, and medical condition of the subject. Thus, insome instances, the dosage regimen actually employed varies and, in someembodiments, deviates from the dosage regimens set forth herein.

For combination therapies described herein, dosages of theco-administered compounds vary depending on the type of co-drugemployed, on the specific drug employed, on the disease or conditionbeing treated and so forth. In additional embodiments, whenco-administered with one or more other therapeutic agents, the compoundprovided herein is administered either simultaneously with the one ormore other therapeutic agents, or sequentially.

In combination therapies, the multiple therapeutic agents (one of whichis one of the compounds described herein) are administered in any orderor even simultaneously. If administration is simultaneous, the multipletherapeutic agents are, by way of example only, provided in a single,unified form, or in multiple forms (e.g., as a single pill or as twoseparate pills). In one embodiment, one of the therapeutic agents isgiven in multiple doses, and in another, two (or more if present) aregiven as multiple doses. In some embodiments of non-simultaneousadministration, the timing between the multiple doses vary from morethan zero weeks to less than four weeks. In addition, the combinationmethods, compositions and formulations are not to be limited to the useof only two agents; the use of multiple therapeutic combinations is alsoenvisioned.

The compounds of Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII),(VIII), (VIIIa), (IX), (IXa) and (X), as well as combination therapiesthat include compounds of Formula (I), (Ia), (II), (III), (IV), (V),(VI), (VII), (VIII), (VIIIa), (IX), (IXa) and (X), are administeredbefore, during or after the occurrence of a disease or condition, andthe timing of administering the composition containing a compoundvaries. Thus, in one embodiment, the compounds described herein are usedas a prophylactic and are administered continuously to subjects with apropensity to develop conditions or diseases in order to prevent theoccurrence of the disease or condition. In another embodiment, thecompounds and compositions are administered to a subject during or assoon as possible after the onset of the symptoms. In specificembodiments, a compound described herein is administered as soon as ispracticable after the onset of a disease or condition is detected orsuspected, and for a length of time necessary for the treatment of thedisease. In some embodiments, the length required for treatment varies,and the treatment length is adjusted to suit the specific needs of eachsubject. For example, in specific embodiments, a compound describedherein or a formulation containing the compound is administered for atleast 2 weeks, about 1 month to about 5 years.

Exemplary Agent for Use in Combination Therapy

In some embodiments, methods for treatment of androgenreceptor-dependent or androgen receptor-mediated conditions or diseases,such as proliferative disorders, including cancer, comprisesadministration to a mammal a compound of Formula (I), (Ia), (II), (III),(IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) incombination with at least one additional agent selected, by way ofexample only, alemtuzumab, arsenic trioxide, asparaginase (pegylated ornon-), bevacizumab, cetuximab, platinum-based compounds such ascisplatin, cladribine, daunorubicin/doxorubicin/idarubicin, irinotecan,fludarabine, 5-fluorouracil, gemtuzumab, methotrexate, taxol,temozolomide, thioguanine, or classes of drugs including hormones (anantiestrogen, an antiandrogen, or gonadotropin releasing hormoneanalogues, interferons such as alpha interferon, nitrogen mustards suchas busulfan or melphalan or mechlorethamine, retinoids such astretinoin, topoisomerase inhibitors such as irinotecan or topotecan,tyrosine kinase inhibitors such as gefinitinib or imatinib, or agents totreat signs or symptoms induced by such therapy including allopurinol,filgrastim, granisetron/ondansetron/palonosetron, dronabinol.

In one aspect, the compound of Formula (I), (Ia), (II), (III), (IV),(V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) is administered orformulated in combination with one or more anti-cancer agents. In someembodiments, one or more of the anti-cancer agents are proapoptoticagents. Examples of anti-cancer agents include, but are not limited to,any of the following: gossypol, genasense, polyphenol E, Chlorofusin,all trans-retinoic acid (ATRA), bryostatin, tumor necrosisfactor-related apoptosis-inducing ligand (TRAIL),5-aza-2′-deoxycytidine, all trans retinoic acid, doxorubicin,vincristine, etoposide, gemcitabine, imatinib, geldanamycin,17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol,LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352,paclitaxel, and analogs of paclitaxel. Compounds that have the basictaxane skeleton as a common structure feature, have also been shown tohave the ability to arrest cells in the G2-M phases due to stabilizedmicrotubules and may be useful for treating cancer in combination withthe compounds described herein.

Further examples of anti-cancer agents for use in combination with thecompounds of Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII),(VIII), (VIIIa), (IX), (IXa) and (X) include inhibitors ofmitogen-activated protein kinase signaling, e.g., U0126, PD98059,PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006,wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies(e.g., rituxan).

Other anti-cancer agents for use in combination with the compounds ofFormula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa),(IX), (IXa) and (X) include one or more of the following: abiraterone,adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin;aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin;altretamine; ambomycin; ametantrone acetate; aminoglutethimide;amsacrine; anastrozole; anthramycin; asparaginase; asperlin;azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide;bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycinsulfate; brequinar sodium; bropirimine; busulfan; cactinomycin;calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicinhydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin;cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin;dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicinhydrochloride; droloxifene; droloxifene citrate; dromostanolonepropionate; duazomycin; edatrexate; eflornithine hydrochloride;elsamitrucin; enloplatin; enpromate; epipropidine; epirubicinhydrochloride; erbulozole; esorubicin hydrochloride; estramustine;estramustine phosphate sodium; etanidazole; etoposide; etoposidephosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide;floxuridine; fludarabine phosphate; fluorouracil; flurocitabine;fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride;hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine;interleukin Il (including recombinant interleukin II, or rlL2),interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferonalfa-n3; interferon beta-1 a; interferon gamma-1 b; iproplatin;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazoie; nogalamycin; ormaplatin; oxisuran; pegaspargase;peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman;piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimersodium; porfiromycin; prednimustine; procarbazine hydrochloride;puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide;safingol; safingol hydrochloride; semustine; simtrazene; sparfosatesodium; sparsomycin; spirogermanium hydrochloride; spiromustine;spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin;tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin;teniposide; teroxirone; testolactone; thiamiprine; thioguanine;thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestoloneacetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate;triptorelin; tubulozole hydrochloride; uracil mustard; uredepa;vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate;vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicinhydrochloride.

Yet other anticancer agents for use in combination with the compounds ofFormula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa),(IX), (IXa) and (X) include alkylating agents, antimetabolites, naturalproducts, or hormones, e.g., nitrogen mustards (e.g., mechloroethamine,cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g.,busulfan), nitrosoureas (e.g., carmustine, lomusitne, ete.), ortriazenes (decarbazine, etc.). Examples of antimetabolites include butare not limited to folic acid analog (e.g., methotrexate), or pyrimidineanalogs (e.g., Cytarabine), purine analogs (e.g., mercaptopurine,thioguanine, pentostatin).

Examples of natural products for use in combination with the compoundsof Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII),(VIIIa), (IX), (IXa) and (X) include but are not limited to vincaalkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins (e.g.,etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin),enzymes (e.g., L-asparaginase), or biological response modifiers (e.g.,interferon alpha).

Examples of alkylating agents for use in combination with the compoundsof Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII),(VIIIa), (IX), (IXa) and (X) include, but are not limited to, nitrogenmustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil,meiphalan, etc.), ethylenimine and methylmelamines (e.g.,hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan),nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin,etc.), or triazenes (decarbazine, ete.).

In some embodiments, compounds of Formula (I), (Ia), (II), (III), (IV),(V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) and (X) are used to treatcancer in combination with: an antiestrogen (e.g., tamoxifen), anantiandrogen (e.g., bicalutamide, flutamide), gonadotropin releasinghormone analog (e.g., leuprolide).

Other agents that can be used in the methods and compositions describedherein for the treatment or prevention of cancer include platinumcoordination complexes (e.g., cisplatin, carboblatin), anthracenedione(e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methylhydrazine derivative (e.g., procarbazine), adrenocortical suppressant(e.g., mitotane, aminoglutethimide).

Examples of anti-cancer agents which act by arresting cells in the G2-Mphases due to stabilized microtubules include without limitation thefollowing marketed drugs and drugs in development: Erbulozole,Dolastatin 10, Mivobulin isethionate, Vincristine, NSC-639829,Discodermolide, ABT-751, Altorhyrtins (such as Altorhyrtin A andAltorhyrtin C), Spongistatins (such as Spongistatin 1, Spongistatin 2,Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6,Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotinhydrochloride, Epothilones (such as Epothilone A, Epothilone B,Epothilone C, Epothilone D, Epothilone E, Epothilone F, Epothilone BN-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothiloneB, 21-hydroxyepothilone D, 26-fluoroepothilone, Auristatin PE,Soblidotin, Vincristine sulfate, Cryptophycin 52, Vitilevuamide,Tubulysin A, Canadensol, Centaureidin, Oncocidin A1 Fijianolide B,Laulimalide, Narcosine, Nascapine, Hemiasterlin, Vanadoceneacetylacetonate, Indanocine Eleutherobins (such asDesmethyleleutherobin, Desaetyleleutherobin, lsoeleutherobin A, andZ-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, DiazonamideA, Taccalonolide A, Diozostatin, (−)-Phenylahistin, Myoseverin B,Resverastatin phosphate sodium.

In one aspect, a compound of Formula (I), (Ia), (II), (III), (IV), (V),(VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) is co-administered withthrombolytic agents (e.g., alteplase anistreplase, streptokinase,urokinase, or tissue plasminogen activator), heparin, tinzaparin,warfarin, dabigatran (e.g., dabigatran etexilate), factor Xa inhibitors(e.g., fondaparinux, draparinux, rivaroxaban, DX-9065a, otamixaban,LY517717, or YM150), ticlopidine, clopidogrel, CS-747 (prasugrel,LY640315), ximelagatran, or BIBR 1048.

In some embodiments, a compound of Formula (I), (Ia), (II), (III), (IV),(V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) is used incombination with anti-emetic agents to treat nausea or emesis, which mayresult from the use of a compound of Formula (I), (Ia), (II), (III),(IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X), anti-canceragent(s) and/or radiation therapy.

Anti-emetic agents include, but are not limited to: neurokinin-1receptor antagonists, 5HT3 receptor antagonists (such as ondansetron,granisetron, tropisetron, Palonosetron, and zatisetron), GABA_(B)receptor agonists (such as baclofen), corticosteroids (such asdexamethasone, prednisone, prednisolone, or others), dopamineantagonists (such as, but not limited to, domperidone, droperidol,haloperidol, chlorpromazine, promethazine, prochlorperazine,metoclopramide), antihistamines (H1 histamine receptor antagonists, suchas but not limited to, cyclizine, diphenhydramine, dimenhydrinate,meclizine, promethazine, hydroxyzine), cannabinoids (such as but notlimited to, cannabis, marinol, dronabinol), and others (such as, but notlimited to, trimethobenzamide; ginger, emetrol, propofol).

In some embodiments, a compound of Formula (I), (Ia), (II), (III), (IV),(V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) is used incombination with an agent useful in the treatment of anemia. Such ananemia treatment agent is, for example, a continuous eythropoiesisreceptor activator (such as epoetin-α).

In some embodiments, a compound of Formula (I), (Ia), (II), (III), (IV),(V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) is used incombination with an agent useful in the treatment of neutropenia.Examples of agents useful in the treatment of neutropenia include, butare not limited to, a hematopoietic growth factor which regulates theproduction and function of neutrophils such as a human granulocytecolony stimulating factor, (G-CSF). Examples of a G-CSF includefilgrastim.

In some embodiments, a compound of Formula (I), (Ia), (II), (III), (IV),(V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) is administeredwith corticosteroids. Corticosteroids, include, but are not limited to:betamethasone, prednisone, alclometasone, aldosterone, amcinonide,beclometasone, betamethasone, budesonide, ciclesonide, clobetasol,clobetasone, clocortolone, cloprednol, cortisone, cortivazol,deflazacort, deoxycorticosterone, desonide, desoximetasone,desoxycortone, dexamethasone, diflorasone, diflucortolone,difluprednate, fluclorolone, fludrocortisone, fludroxycortide,flumetasone, flunisolide, fluocinolone acetonide, fluocinonide,fluocortin, fluocortolone, fluorometholone, fluperolone, fluprednidene,fluticasone, formocortal, halcinonide, halometasone,hydrocortisone/cortisol, hydrocortisone aceponate, hydrocortisonebuteprate, hydrocortisone butyrate, loteprednol, medrysone,meprednisone, methylprednisolone, methylprednisolone aceponate,mometasone furoate, paramethasone, prednicarbate,prednisone/prednisolone, rimexolone, tixocortol, triamcinolone, andulobetasol.

In one embodiment, a compound of Formula (I), (Ia), (II), (III), (IV),(V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) is administered toa mammal in combination with a non-steroidal anti-inflammatory drug(NSAID). NSAIDs include, but are not limited to: aspirin, salicylicacid, gentisic acid, choline magnesium salicylate, choline salicylate,choline magnesium salicylate, choline salicylate, magnesium salicylate,sodium salicylate, diflunisal, carprofen, fenoprofen, fenoprofencalcium, flurobiprofen, ibuprofen, ketoprofen, nabutone, ketolorac,ketorolac tromethamine, naproxen, oxaprozin, diclofenac, etodolac,indomethacin, sulindac, tolmetin, meclofenamate, meclofenamate sodium,mefenamic acid, piroxicam, meloxicam, COX-2 specific inhibitors (suchas, but not limited to, celecoxib, rofecoxib, valdecoxib, parecoxib,etoricoxib, lumiracoxib, CS-502, JTE-522, L-745,337 and NS398).

In some embodiments, compounds of Formula (I), (Ia), (II), (III), (IV),(V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) and (X) arecoadministered with analgesics.

In some embodiments, a compound of Formula (I), (Ia), (II), (III), (IV),(V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) is used incombination with radiation therapy (or radiotherapy). Radiation therapyis the treatment of cancer and other diseases with ionizing radiation.Radiation therapy can be used to treat localized solid tumors, such ascancers of the skin, tongue, larynx, brain, breast, prostate, colon,uterus and/or cervix. It can also be used to treat leukemia and lymphoma(cancers of the blood-forming cells and lymphatic system, respectively).

A technique for delivering radiation to cancer cells is to placeradioactive implants directly in a tumor or body cavity. This is calledinternal radiotherapy (brachytherapy, interstitial irradiation, andintracavitary irradiation are types of internal radiotherapy.) Usinginternal radiotherapy, the radiation dose is concentrated in a smallarea, and the patient stays in the hospital for a few days. Internalradiotherapy is frequently used for cancers of the tongue, uterus,prostate, colon, and cervix.

The term “radiotherapy” or “ionizing radiation” include all forms ofradiation, including but not limited to α, β, and γ radiation andultraviolet light.

Kits/Articles of Manufacture

For use in the therapeutic applications described herein, kits andarticles of manufacture are also described herein. Such kits cancomprise a carrier, package, or container that is compartmentalized toreceive one or more containers such as vials, tubes, and the like, eachof the container(s) comprising one of the separate elements to be usedin a method described herein. Suitable containers include, for example,bottles, vials, syringes, and test tubes. The containers are formed fromany acceptable material including, e.g., glass or plastic.

For example, the container(s) can comprise one or more compoundsdescribed herein, optionally in a composition or in combination withanother agent as disclosed herein. The container(s) optionally have asterile access port (for example the container can be an intravenoussolution bag or a vial having a stopper pierceable by a hypodermicinjection needle). Such kits optionally comprising a compound with anidentifying description or label or instructions relating to its use inthe methods described herein.

A kit will typically comprise one or more additional containers, eachwith one or more of various materials (such as reagents, optionally inconcentrated form, and/or devices) desirable from a commercial and userstandpoint for use of a compound described herein. Non-limiting examplesof such materials include, but not limited to, buffers, diluents,filters, needles, syringes; carrier, package, container, vial and/ortube labels listing contents and/or instructions for use, and packageinserts with instructions for use. A set of instructions will alsotypically be included.

A label can be on or associated with the container. A label can be on acontainer when letters, numbers or other characters forming the labelare attached, molded or etched into the container itself; a label can beassociated with a container when it is present within a receptacle orcarrier that also holds the container, e.g., as a package insert. Alabel can be used to indicate that the contents are to be used for aspecific therapeutic application. The label can also indicate directionsfor use of the contents, such as in the methods described herein.

EXAMPLES

These examples are provided for illustrative purposes only and not tolimit the scope of the claims provided herein.

Synthesis of Compounds

Intermediate 1 5-Amino-3-(trifluoromethyl)picolinonitrile Step 1:5-Iodo-3-(trifluoromethyl)pyridin-2-ol

A mixture of 5-iodo-3-(trifluoromethyl)pyridin-2-ol (21.4 g, 0.13 mmol)and NIS (29.5 g, 0.13 mmol) in acetonitrile (300 mL) was heated to 80°C. for 6 h. The reaction mixture was cooled to room temperature and asaturated solution of sodium bicarbonate was added. The solid thatprecipitated was filtered off and acetonitrile was removed in vacuo. Theaqueous layer was extracted with EtOAc (4×), the organics were combined,washed with an aqueous saturated solution of sodium thiosulfate, driedover sodium sulfate, and concentrated to dryness to afford 24 g of5-iodo-3-(trifluoromethyl)pyridin-2-ol as a yellow solid. ¹H NMR (300MHz, DMSO-d₆) δ 12.57 (s, 1H), 8.01 (s, 1H), 7.99 (s, 1H).

Step 2: 2-Chloro-5-iodo-3-(trifluoromethyl)pyridine

A mixture of 5-iodo-3-(trifluoromethyl)pyridin-2-ol (53 g, 0.18 mmol)and POCl₃ (67 mL, 0.73 mmol) in DMF (50 mL) was heated to 110° C. for 4h. The reaction mixture was cooled to room temperature and then slowlypoured into an ice/water bath. The brown solid was filtered and washedwith water. It was then dissolved in DCM, washed with an aqueoussaturated solution of sodium thiosulfate (2×), dried over sodiumsulfate, and concentrated to dryness to afford 47 g of2-chloro-5-iodo-3-(trifluoromethyl)pyridine as a pale yellow solid. ¹HNMR (300 MHz, DMSO-d₆) δ 8.79 (d, 1H), 8.29 (d, 1H).

Step 3: 6-Chloro-N-(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-3-amine

An oil bath was preheated to 130° C. A mixture of2-chloro-5-iodo-3-(trifluoromethyl)pyridine (47 g, 152.8 mmol),(4-methoxyphenyl)methanamine (23.8 mL, 183.4 mmol), Xantphos (2.6 g,4.58 mmol) and NaOtBu (22 g, 229.2 mmol) in toluene (500 mL) was stirredat room temperature while bubbling nitrogen for 5 min Pd₂(dba)₃ (2.8 g,3.05 mmol) was then added and the reaction mixture was refluxed for 2 h.The mixture was cooled to room temperature and it was filtered through apad of celite. The pad of celite was washed with toluene and thefiltrate was concentrated. The residue obtained was dissolved in EtOAc,the organic layer was washed with water (4×), and it was then evaporatedto dryness. The dark oil obtained was dissolved in DCM and hexanes wasadded with swirling until a brown solid precipitated. The brown solidwas filtered, washed with hexanes, and dried to afford 38.8 g (80%) of6-chloro-N-(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-3-amine as abrown solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.96 (d, 1H), 7.38 (d, 1H),7.29 (d, 2H), 7.07 (t, 1H), 6.92 (d, 2H), 4.29 (d, 2H), 3.73 (s, 3H).The filtrate was purified by column chromatography on Silica Gel elutingwith 0 to 50% EtOAc/Hexanes to afford an additional 4 g of6-chloro-N-(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-3-amine as anorange solid (Total yield: 42.8 g).

Step 4: 5-((4-Methoxybenzyl)amino)-3-(trifluoromethyl)picolinonitrile

An oil bath was preheated to 180° C. A mixture of6-chloro-N-(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-3-amine (19.45g, 61.55 mmol), Zn(CN)₂ (8.7 g, 73.86 mmol), and dppf (6.8 g, 12.31mmol) in DMF (250 mL) was stirred at room temperature while bubblingnitrogen for 5 min Pd₂(dba)₃ (2.8 g, 3.07 mmol, 0.05 eq.) was then addedand the reaction mixture was placed inside the pre-heated bath. The bathtemperature dropped to 160° C. The mixture started refluxing when thebath temperature reached 170° C. (takes 20 min) Refluxed for 10 min. Thereaction mixture was cooled to room temperature and it was filteredthrough a pad of celite. The pad of celite was washed with EtOAc. Thesolvent was removed using a rotovap hooked up to a high vac. pump. Theblack residue was partitioned between EtOAc and water. An orange solid(some dppf by-product) precipitated and was filtered and washed withEtOAc. The organic layer was washed with brine (2×), dried over sodiumsulfate, and concentrated to dryness. The black residue was dissolved inDCM and loaded onto a silica gel plug. The plug was washed with DCM (toget rid of some of the fast eluting impurities) followed by 1:1EtOAc/hexanes (to move the desired). The fractions containing thedesired were combined, evaporated to dryness and the residue obtainedwas purified by column chromatography on silica gel eluting with 0 to50% EtOAc/hexanes to afford 15 g of5-((4-methoxybenzyl)amino)-3-(trifluoromethyl)picolinonitrile as reddishthick oily residue. ¹H NMR (300 MHz, DMSO-d₆) δ 8.28 (s, 1H), 8.01 (t,1H), 7.31 (m, 3H), 6.92 (d, 2H), 4.41 (d, 2H), 3.73 (s, 3H).

Step 5: 5-Amino-3-(trifluoromethyl)picolinonitrile

5-((4-Methoxybenzyl)amino)-3-(trifluoromethyl)picolinonitrile (15 g,49.02 mmol) was taken up in DCM (30 mL) and TFA (50 mL) was added. Theresulting reaction mixture was stirred at room temperature for 3 h(until done by LC-MS). The solvent and TFA were removed in vacuo andMeOH was added to the residue. The beige solid that was not soluble inMeOH was filtered and washed with MeOH. The filtrate was evaporated todryness and the residue was partitioned between EtOAc and a saturatedsolution of sodium bicarbonate. The organic layer was washed two moretimes with a saturated aqueous sodium bicarbonate, dried over sodiumsulfate, and evaporated to dryness. The residue was dissolved in DCM andhexanes with swirling until a yellow solid precipitated. This solid wasfiltered and washed with hexanes to afford 7.2 g of5-amino-3-(trifluoromethyl)picolinonitrile as a pale yellow solid. ¹HNMR (300 MHz, DMSO-d₆) δ 8.17 (d, 1H), 7.28 (d, 1H), 6.99 (bs, 2H).

Intermediate 2 5-Amino-3-methylpicolinonitrile Step 1:3-Methyl-5-nitropicolinonitrile

A mixture of tetrabutylammonium nitrate (17 g, 55.1 mmol) andtrifluoroacetic anhydride (7.6 mL, 55.1 mmol) in DCM (50 mL) was slowlyadded to a cooled (0° C.) solution of 3-methylpicolinonitrile (5 g, 42.4mmol) in DCM (100 mL) and the resulting mixture was stirred for 3 days(temperature allowed to warm to room temperature). A saturated solutionof sodium bicarbonate (80 mL) was added and the mixture was stirred atroom temperature for 1 h. The two layers were separated and the aqueouswas extracted with DCM (2×). The organics were combined, dried oversodium sulfate, and concentrated to dryness. The residue was purified bycolumn chromatography on silica gel eluting with 0 to 50% EtOAc/hexanesto afford 2.9 g of 3-methyl-5-nitropicolinonitrile as a pale yellowsolid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.32 (s, 1H), 8.83 (s, 1H), 2.64 (s,3H).

Step 2: 5-Amino-3-methylpicolinonitrile

A mixture of 3-methyl-5-nitropicolinonitrile (2.9 g, 17.8 mmol) and Pd/C(cat.) in MeOH (60 mL) was hydrogenated overnight with a balloon ofhydrogen. Pd/C was removed through a pad of celite and the filtrate wasevaporated to dryness to afford 2.2 g of 5-amino-3-methylpicolinonitrileas a greenish solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.83 (s, 1H), 6.79 (s,1H), 6.32 (s, 2H), 2.29 (s, 3H).

Intermediate 33-(Trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-amine Step 1:6-Chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine

A mixture of 3-chloro-6-hydrazinylpyridazine (3.3 g, 22.8 mmol) in TFA(60 mL) was heated to 85° C. for 18 h. The reaction mixture was cooledto room temperature and TFA was removed in vacuo. The residue waspartitioned between DCM and saturated aqueous sodium bicarbonate and theorganic layer was washed with a saturated solution of sodium bicarbonate(3×), dried over sodium sulfate, and evaporated to dryness to afford 2.8g of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine as abeige solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.72 (d, 1H), 7.78 (d, 1H).

Step 2: 3-(Trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-amine

A mixture of6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (1.14 g,5.1 mmol) and ammonium hydroxide (10 mL) in THF (10 mL) was heated to60° C. for 18 h. The reaction mixture was cooled to room temperature andwater and EtOAc were added. The aqueous layer was extracted with EtOAc(4×), the organics were combined, dried over sodium sulfate, andevaporated to dryness to afford 1 g of3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-amine as beigesolid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.12 (d, 1H), 7.23 (s, 2H), 6.97 (d,1H).

Intermediate 4 6-Amino-2-(trifluoromethyl)nicotinonitrile

A mixture of 5-bromo-6-(trifluoromethyl)pyridin-2-amine (3.0 g, 12.3mmol), Zn(CN)₂ (0.81 g, 6.9 mmol), Pd₂(dba)₃ (0.57 g, 0.6 mmol), andXantphos (0.72 g, 1.2 mmol) in DMA (12 mL) was placed in a sealed tube.The mixture was degassed with argon and stirred at 160° C. for 20 h. Themixture was poured into water and extracted with EtOAc (2×). Thecombined organic layers were dried over magnesium sulfate andconcentrated to dryness. The residue was purified by columnchromatography on silica gel eluting with 3:1 EtOAc/hexanes to afford1.9 g of 6-amino-2-(trifluoromethyl)nicotinonitrile as a solid. ¹H NMR(400 MHz, CDCl₃) δ 7.74 (d, 1H), 6.67 (d, 1H).

Intermediate 5 3-(Trifluoromethyl)-[2,3′-bipyridin]-5-amine Step 1:N-(4-Methoxybenzyl)-3-(trifluoromethyl)-[2,3′-bipyridin]-5-amine

To a solution of6-chloro-N-(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-3-amine(Intermediate 1, Step 3, 1.2 g, 3.8 mmol) and 3-(diethylboryl)pyridine(0.613 g, 4.17 mmol) in 1,4-dioxane (100 mL) was added K₃PO₄ (2.52 g,9.48 mmol). The mixture was degassed then flushed with nitrogen beforePd₂(dba)₃ (173 mg, 0.02 mmol) and Xantphos (0.218 mg, 0.04 mmol) wereadded. The mixture was heated at 105° C. overnight. The reaction mixturewas cooled to room temperature and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by columnchromatography on silica gel using EtOAc/PE=1/to afford 1 g ofN-(4-methoxybenzyl)-3-(trifluoromethyl)-[2,3′-bipyridin]-5-amine.

Step 2: 3-(Trifluoromethyl)-[2,3′-bipyridin]-5-amine

The title compound was synthesized as described for Intermediate 1, Step5 using N-(4-methoxybenzyl)-3-(trifluoromethyl)-[2,3′-bipyridin]-5-amineas the starting material. ¹H NMR (300 MHz, CDCl₃) δ 8.71 (dd, 1H), 8.64(dd, 1H), 8.30 (dd, 1H), 7.78 (m, 1H), 7.35 (m, 1H), 7.32 (d, 1H), 4.05(s, 2H).

Intermediate 6 (Isothiocyanate Method A)5-Isothiocyanato-3-methylpicolinonitrile

Thiophosgene (0.24 mL, 3.1 mmol) was added to a stirred biphasicsolution of 5-amino-3-methylpicolinonitrile (Intermediate 2, 275 mg,2.07 mmol) in CHCl₃ (6 mL)/water (10 mL) and the resulting orangemixture was stirred at room temperature overnight. The two layers wereseparated and the aqueous layer was extracted with DCM (3×). Theorganics were combined, washed with a saturated solution of sodiumbicarbonate (2×), dried over sodium sulfate, and evaporated to drynessto afford 300 mg of 5-isothiocyanato-3-methylpicolinonitrile as anorange solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.66 (s, 1H), 8.06 (s, 1H),2.5 (s, 3H).

Intermediate 7 6-Isothiocyanato-2-(trifluoromethyl)nicotinonitrile

A mixture of 6-amino-2-(trifluoromethyl)nicotinonitrile (648 mg, 3.5mmol) and thiophosgene (0.4 mL, 5.2 mmol) in DCE (8 mL) was heated to80° C. overnight. The mixture was cooled to room temperature and dilutedwith DCM/water. The two layers were separated and the aqueous layer wasextracted with DCM (3×). The organics were combined, washed with asaturated solution of sodium bicarbonate (2×), dried over sodiumsulfate, and evaporated to dryness to afford 521 mg of6-isothiocyanato-2-(trifluoromethyl)nicotinonitrile (70% pure) as abrown oil. ¹H NMR (300 MHz, DMSO-d₆) δ 8.73 (d, 1H), 7.93 (d, 1H).

Intermediate 86-Isothiocyanato-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine

Thiophosgene (1 mL, 12.7 mmol) was added to a solution of3-(trifluoromethyl)-[1,2,4]-triazolo[4,3-b]pyridazin-6-amine (860 mg,4.23 mmol) in pyridine (10 mL) and THF (15 mL) and the resulting darkmixture was stirred at room temperature for 2 h. The dark mixture waspartitioned between EtOAc and 1M HCl. The organic layer was washed with1M HCl (2×), dried over sodium sulfate, and evaporated to dryness toafford 545 mg (60% pure) of6-isothiocyanato-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine asa dark purple solid. LCMS [M+1]⁺278.5 (OMe adduct).

Intermediate 9 (Isothiocyanate Method B)4-Isothiocyanatoisoquinoline-1-carbonitrile

A mixture of 4-aminoisoquinoline-1-carbonitrile (500 mg, 2.95 mmol) andthiophosgene (0.34 mL, 4.44 mmol) in DMA (5 mL) was stirred at roomtemperature overnight. The mixture was diluted with EtOAc/water. The twolayers were separated and the aqueous layer was extracted with EtOAc(3×). The organics were combined, washed with a saturated solution ofsodium bicarbonate (2×), dried over sodium sulfate, and evaporated todryness to afford 553 mg of 4-isothiocyanatoisoquinoline-1-carbonitrileas an orange oil. ¹H NMR (300 MHz, DMSO-d₆) δ 8.88 (s, 1H), 8.32 (d,1H), 8.23 (d, 1H), 8.12 (td, 1H), 8.05 (td, 1H).

ISOTHIOCYANATE INTERMEDIATES 10-16 were synthesized from the appropriateamines (amines were either commercially available, synthesized in theIntermediates section, or synthesized from published procedures)according to the conditions indicated (see footnotes).

Inter- mediate # Name Structure 10^(a) 5-Isothiocyanato-3-(trifluoromethyl) picolinonitrile

11^(a) 3-Chloro-5- isothiocyanato- picolinonitrile

12^(a) 5-Isothiocyananto- 3-methoxy- picolinonitrile

13^(a) 5-Isothiocyanato- quinoline-8- carbonitrile

14^(a) 6-Isothio- cyanatoimidazo [1,2-a]pyridine

15^(a) 5-Isothiocyanato- 3-(trifluoromethyl)- 2,3′- bipyridine

16^(b) 4-Isothio- cyanatopyrazolo [1,5-a]pyridine-7- carbonitrile

^(a)Isothiocyanate method A, ^(b)Isothiocyanate method B

Intermediate 17 4-((2-(Pyridin-4-yl)ethyl)sulfonyl)aniline Step 1:4-(2-((4-Nitrophenyl)thio)ethyl)pyridine

A mixture of 2-(pyridin-4-yl)ethanethiol hydrochloride (3.84 g, 21.8mmol, 4-fluoro-1-nitrobenzene (6.12 g, 43.3 mmol), and K₂CO₃ (9.0 g,65.1 mmol) in acetonitrile (150 mL) was refluxed overnight. The reactionmixture was filtered and the filtrate was concentrated to dryness. Theresidue was purified by column chromatography on silica gel(EtOAc/PE=1/1) to afford 2.0 g of4-(2-((4-nitrophenyl)thio)ethyl)pyridine as a light yellow solid. ¹H NMR(300 MHz, CDCl₃) δ 8.55 (d, 2H), 8.14 (d, 2H), 7.34 (d, 2H), 7.15 (d,2H), 3.30 (t, 2H), 3.01 (t, 2H).

Step 2: 4-(2-((4-Nitrophenyl)sulfonyl)ethyl)pyridine

H₂O₂ (30%, 5 mL) was added dropwise to a solution of4-(2-((4-nitrophenyl)thio)ethyl)pyridine (338 mg, 1.30 mmol) in aceticacid (20 mL) heated at 60° C. and the resulting mixture was stirred at60° C. for 30 min. The mixture was poured into a sat. Na₂CO₃ (100 mL)and extracted with DCM. The organic layer was dried over sodium sulfateand concentrated to dryness. The residue was purified by columnchromatography on silica gel (EA/PE=1/3) to afford 270 mg of4-(2-((4-nitrophenyl)sulfonyl)ethyl)pyridine as a white solid. ¹H NMR(300 MHz, CDCl₃) δ 8.51 (d, 2H), 8.42 (dd, 2H), 7.13 (dd, 2H), 7.08 (d,2H), 3.45-3.40 (m, 2H), 3.14-3.08 (m, 2H).

Step 3: 4-((2-(Pyridin-4-yl)ethyl)sulfonyl)aniline

A mixture of 4-(2-((4-nitrophenyl)sulfonyl)ethyl)pyridine (210 mg, 0.76mmol) and 10% Pd/C (100 mg) in EtOH (100 mL) was stirred at roomtemperature for 3 h under H₂ atmosphere (balloon). The reaction mixturewas filtered and the filtrate was concentrated to dryness. The residuewas purified by column chromatography on silica gel (MeOH/DCM=1/50) toafford 100 mg of 4-((2-(pyridin-4-yl)ethyl)sulfonyl)aniline as a whitesolid. ¹H NMR (300 MHz, CDCl₃) δ 8.48 (m, 2H), 7.67 (m, 2H), 7.05 (m,2H), 6.70 (m, 2H), 4.23 (bs, 2H), 3.34-3.28 (m, 2H), 3.07-3.01 (m, 2H).

Intermediate 18 4-((Methyl(pyridin-4-ylmethyl)amino)methyl)aniline Step1: N-(4-Nitrobenzyl)-1-(pyridin-4-yl)methanamine

A mixture of 4-nitrobenzaldehyde (3.0 g, 19.8 mmol),4-pyridylmethylamine (2.36 g, 21.8 mmol), and NaBH₃CN (1.75 g, 27.7mmol) in 1,2-dichloroethane (40.0 mL) was stirred at room temperaturefor 36 h and then concentrated to dryness. The residue was partitionedbetween water and EtOAc. The aqueous layer was extracted with EtOAc(3×). The combined organics were washed with brine (2×), dried oversodium sulfate, and concentrated. The residue was purified by columnchromatography on silica gel (MeOH/DCM=1/400) to afford 1.3 g ofN-(4-nitrobenzyl)-1-(pyridin-4-yl)methanamine as brown oil.

Step 2: N-Methyl-N-(4-nitrobenzyl)-1-(pyridin-4-yl)methanamine

The title compound was synthesized as described in the previous stepusing N-(4-nitrobenzyl)-1-(pyridin-4-yl)methanamine and (HCHO)n as thestarting materials.

Step 3: 4-((Methyl(pyridin-4-ylmethyl)amino)methyl)aniline

The title compound was synthesized as described for Intermediate 17,Step 3 using N-methyl-N-(4-nitrobenzyl)-1-(pyridin-4-yl)methanamine asthe starting material.

Intermediate 19 (Aminonitrile Synthesis Method A)1-((3-Fluoro-4-hydroxyphenyl)amino)cyclobutanecarbonitrile

Sodium cyanide (2.5 g, 50.8 mmol) was added to a mixture of4-amino-2-fluorophenol (4.3 g, 33.9 mmol) and cyclobutanone (3.8 mL,50.8 mmol) in acetic acid (99%, 30 mL) hooked up to a NaOH scrubber andthe resulting mixture was stirred at room temperature for 6 h. Themixture was poured in water and the aqueous layer was extracted withEtOAc (3×). The organics were combined, washed with a saturated solutionof sodium bicarbonate (4×), dried over sodium sulfate, and evaporated todryness. The residue was purified by column chromatography on silica geleluting with 0 to 50% EtOAc/hexanes to afford 4.8 g of1-((3-fluoro-4-hydroxyphenyl)amino)cyclobutanecarbonitrile as a beigesolid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.98 (s, 1H), 6.80 (t, 1H), 6.36 (dd,1H), 6.28 (m, 2H), 2.71-2.62 (m, 2H), 2.35-2.25 (m, 2H), 2.12-2.00 (m,2H).

Intermediate 20 (Aminonitrile Synthesis Method B) Ethyl4-((1-cyanocyclobutyl)amino)-2-fluorobenzoate

Sodium cyanide (1.3 g, 26.6 mmol) was added to a mixture of ethyl4-amino-2-fluorobenzoate (3.25 g, 17.8 mmol) and cyclobutanone (2 mL,26.6 mmol) in acetic acid (99%, 40 mL) hooked up to a NaOH scrubber andthe resulting mixture was heated to 80° C. overnight. The mixture wascooled to room temperature and poured in water. The pink precipitate wasfiltered, washed with water, and redissolved in DCM (100 mL). Theorganic layer was washed with a saturated solution of sodium bicarbonate(4×), dried over sodium sulfate, and evaporated to dryness to afford 3.9g of ethyl 4-((1-cyanocyclobutyl)amino)-2-fluorobenzoate as an orangesolid. ¹H NMR (300 MHz, CDCl₃) δ 7.87 (t, 1H), 6.43 (dd, 1H), 6.34 (dd,1H), 4.55 (s, 1H), 4.36 (q, 2H), 2.91-2.82 (m, 2H), 2.46-2.30 (m, 2H),2.28-2.13 (m, 2H), 1.39 (t, 3H).

Intermediate 21 (Aminonitrile Synthesis Method C)4-((1-Cyanocyclobutyl)amino)-2-fluoro-N-methylbenzamide

Sodium cyanide (5.8 g, 119 mmol) was added to a mixture of4-amino-2-fluoro-N-methylbenzamide (5 g, 29.8 mmol) and cyclobutanone(4.4 mL, 59.5 mmol) in AcOH (90%, 25 mL) and EtOH (25 mL) hooked up to aNaOH scrubber and the resulting mixture was heated to 80° C. overnight.The mixture was cooled to room temperature and poured in water. Theyellow precipitate was filtered, washed with water, and dried to afford6.5 g of 4-((1-cyanocyclobutyl)amino)-2-fluoro-N-methylbenzamide as apale yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.81 (t, 1H), 7.56 (t,1H), 7.37 (s, 1H), 6.46 (dd, 1H), 6.30 (dd, 1H), 2.80-2.71 (m, 5H),2.41-2.31 (m, 2H), 2.13-2.00 (m, 2H)

Intermediate 22 (Aminonitrile Synthesis Method D)1-((2,6-Difluorophenyl)amino)cyclobutanecarbonitrile

A mixture of 2,6-difluoroaniline (0.5 g, 3.9 mmol), TMSCN (0.72 mL, 5.8mmol), and cyclobutanone (0.43 mL, 5.8 mmol) was heated to 90° C.overnight. The mixture was poured in water and the aqueous layer wasextracted with EtOAc (3×). The organics were combined, washed withbrine. (2×), dried over sodium sulfate, and evaporated to dryness. Theresidue was purified by column chromatography on silica gel eluting with0 to 20% EtOAc/hexanes to afford 0.7 g of1-((2,6-difluorophenyl)amino)cyclobutanecarbonitrile as a colorless oil.¹H NMR (300 MHz, DMSO-d₆) δ 7.07-7.01 (m, 2H), 6.91-6.81 (m, 1H), 6.15(s, 1H), 2.65-2.56 (m, 2H), 2.52-2.42 (m, 2H), 2.01-1.91 (m, 2H).

Intermediate 23 (Aminonitrile Synthesis Method E)4-((2-Cyanopropan-2-yl)amino)-2-fluoro-N-methylbenzamide

A mixture of 4-amino-2-fluoro-N-methylbenzamide (2 g, 11.9 mmol), TMSCN(2.2 mL, 17.9 mmol), TMSOTf (0.1 mL, 0.6 mmol), and acetone (10 mL, 140mmol) in DCM (20 mL) was stirred at room temperature overnight. Thewhite solid was filtered, washed with a small amount of DCM, and driedto afford 1.12 g of4-((2-cyanopropan-2-yl)amino)-2-fluoro-N-methylbenzamide as a whitesolid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.79 (t, 1H), 7.56 (t, 1H), 6.88 (s,1H), 6.67 (dd, 1H), 6.54 (dd, 1H), 2.75 (d, 3H), 1.67 (s, 6H).

Intermediate 241-(4-(Pyridin-4-yloxy)phenylamino)cyclobutanecarbonitrile

Sodium cyanide (395 mg, 8.06 mmol) was added to a mixture of4-(pyridin-4-yloxy)aniline (500 mg, 2.69 mmol) and cyclobutanone (376mg, 5.37 mmol) in AcOH (99%, 6 mL) in a microwave vial. The reactionmixture was irradiated with microwaves (Biotage) at 120° C. for 30 min.The slightly yellowish solution was concentrated to dryness. The residuewas diluted with water and extracted with EtOAc (2×). The combinedorganic layers were dried over MgSO₄ and concentrated to dryness toafford 463 mg (65%) of1-(4-(pyridin-4-yloxy)phenylamino)-cyclobutanecarbonitrile as a yellowoil. ¹H NMR (400 MHz, CDCl₃) δ 8.46-8.38 (m, 2H), 7.02-6.94 (m, 2H),6.79 (m, 2H), 6.72-6.64 (m, 2H), 2.86-2.74 (m, 2H), 2.46-2.34 (m, 2H),2.22 (m, 2H)

Intermediate 25 2-((4-Hydroxyphenyl)amino)-2-methylpropanenitrile

A mixture of 4-aminophenol (1 g, 9.17 mmol) and magnesium sulfate (4 g)in 2-hydroxy-2-methylpropanenitrile (10 mL) was heated to 80° C. for 2h. Ice/water was added to a cooled mixture and it was stirred for 30min. The white solid that precipitated was filtered, washed with water,and dried to afford 1.2 g (74%) of2-((4-hydroxyphenyl)amino)-2-methylpropanenitrile as a white solid. ¹HNMR (400 MHz, CDCl₃) δ 8.89 (s, 1H), 6.78 (d, 2H), 6.65 (d, 2H), 5.21(s, 1H), 1.52 (s, 6H).

INTERMEDIATES 26-107 were synthesized from the appropriate amines(amines were either commercially available, synthesized in theIntermediates section, or synthesized from published procedures) andketones, according to the conditions indicated (see footnotes).

Intermediate # Name Structure  26 ^(a) 1-((2-Fluoro-4-hydroxyphenyl)amino) cyclobutanecarbonitrile

 27 ^(b) 1-((4-Fluoro-3- methoxyphenyl)amino) cyclobutanecarbonitrile

 28 ^(b) 1-([1,1′-Biphenyl]-2- ylamino) cyclobutanecarbonitrile

 29 ^(b) 1-([1,1′-Biphenyl]-3- ylamino) cyclobutanecarbonitrile

 30 ^(b) 1-([1,1′-Biphenyl]-4- ylamino) cyclobutanecarbonitrile

 31 ^(b) 1-(Naphthalen-1- ylamino) cyclobutanecarbonitrile

 32 ^(b) 1-(Naphthalen-2- ylamino) cyclobutanecarbonitrile

 33 ^(b) Ethyl 5-((1-cyanocyclobutyl) amino)-2- fluorobenzoate

 34 ^(b) 2-((1-Cyanocyclobutyl) amino)benzonitrile

 35 ^(b) 3-((1-Cyanocyclobutyl) amino)benzonitrile

 36 ^(b) 4-((1-(Cyanocyclobutyl) amino)benzonitrile

 37 ^(b) 1-(Pyridin-3-ylamino) cyclobutanecarbonitrile

 38 ^(c) 1-(o-Tolylamino) cyclobutanecarbonitrile

 39 ^(c) 1-(m-Tolylamino) cyclobutanecarbonitrile

 40 ^(c) 1-(p-Tolylamino) cyclobutanecarbonitrile

 41 ^(b) 1-((4-Fluoro-2- methoxyphenyl)amino) cyclobutanecarbonitrile

 42 ^(b) 1-((4-Fluoro-2- hydroxyphenyl)amino) cyclobutanecarbonitrile

 43 ^(d) 1-((2- Phenoxyphenyl)amino) cyclobutanecarbonitrile

 44 ^(b) 1-((3- Phenoxyphenyl)amino) cyclobutanecarbonitrile

 45 ^(b) 1-((4- Phenoxyphenyl)amino) cyclobutanecarbonitrile

 46 ^(d) 1-((4- Methylbenzyl)amino) cyclobutanecarbonitrile

 47 ^(d) 1-((4- Methylphenethyl)amino) cyclobutanecarbonitrile

 48 ^(d) 1-((4-(Pyridin-3- yloxy)phenyl)amino) cyclobutanecarbonitrile

 49 ^(b) 1-((4-(Pyridin-2- yloxy)phenyl)amino) cyclobutanecarbonitrile

 50 ^(b) 1-((4-(Pyrimidin-5- yloxy)phenyl)amino) cyclobutanecarbonitrile

 51 ^(b) 1-((3- (Trifluoromethoxy)phenyl) amino)cyclobutanecarbonitrile

 52 ^(b) 1-((4- (Trifluoromethoxy)phenyl) amino)cyclobutanecarbonitrile

 53 ^(b) 1-((2- Fluorophenyl)amino) cyclobutanecarbonitrile

 54 ^(b) 1-((3- Fluorophenyl)amino) cyclobutanecarbonitrile

 55 ^(b) 1-((4- Fluorophenyl)amino) cyclobutanecarbonitrile

 56 ^(c) 1-((4- (Trifluoromethyl)phenyl) amino)cyclobutanecarbonitrile

 57 ^(b) 1-(Phenylamino) cyclobutanecarbonitrile

 58 ^(b) 1-((3-Fluoro-4- methylphenyl)amino) cyclobutanecarbonitrile

 59 ^(b) 1-((2-Fluoro-4- methylphenyl)amino) cyclobutanecarbonitrile

 60 ^(b) 1-(Cyclohexylamino) cyclobutanecarbonitrile

 61 ^(b) 1-((4- (Methylsulfonyl)phenyl) amino) cyclobutanecarbonitrile

 62 ^(b) 4-((1- Cyanocyclobutyl) amino)benzenesulfonamide

 63 ^(b) 1-(Isoquinolin-6- ylamino) cyclobutanecarbonitrile

 64 ^(b) 1-(Isoquinolin-7- ylamino) cyclobutanecarbonitrile

 65 ^(b) 4-((1- Cyanocyclobutyl)amino)- 2-fluorobenzonitrile

 66 ^(b) 4-((1-Cyanocyclobutyl)amino)- 3-fluorobenzonitrile

 67 ^(c) 1-((2- (Hydroxymethyl)phenyl) amino)cyclobutanecarbonitrile

 68 ^(c) 1-((3- (Hydroxymethyl)phenyl) amino)cyclobutanecarbonitrile

 69 ^(c) 1-((4- (Hydroxymethyl)phenyl) amino)cyclobutanecarbonitrile

 70 ^(b) 4-((1-Cyanocyclobutyl) amino)-3-fluoro-N- methylbenzamide

 71 ^(c) Methyl 4-((1-cyano- cyclobutyl)amino)-3- fluorobenzoate

 72 ^(d) 1-((2,3- Difluorophenyl) amino)cyclobutanecarbonitrile

 73 ^(d) 1-((2,5- Difluorophenyl)amino) cyclobutanecarbonitrile

 74 ^(d) 1-((2,3,6- Trifluorophenyl)amino) cyclobutanecarbonitrile

 75 ^(d) 1-((2,4- Difluorophenyl)amino) cyclobutanecarbonitrile

 76 ^(c) 2-Methyl-2-(p- tolylamino)propanenitrile

 77 ^(c) 1-((1H-Indazol-5- yl)amino) cyclobutanecarbonitrile

 78 ^(c) 1-((1H-Indazol-6- yl)amino) cyclobutanecarbonitrile

 79 ^(e) 1-(Benzo[d]oxazol-6- ylamino) cyclobutanecarbonitrile

 80 ^(b) 4-(4-((1- Cyanocyclobutyl)amino) phenyl)butanoic acid

 81 ^(b) 1-((4-(3- Hydroxypropyl)phenyl) amino)cyclobutanecarbonitrile

 82 ^(e) 1-((4-(4-Methylpiperazin- 1-yl)phenyl)amino)cyclobutanecarbonitrile

 83 ^(e) 1-((4-(Pyridin-4- yl)phenyl)amino) cyclobutanecarbonitrile

 84 ^(e) 1-((4-(Pyridin-3- yl)phenyl)amino) cyclobutanecarbonitrile

 85 ^(e) 1-((4-(pyridin-2- yl)phenyl)amino) cyclobutanecarbonitrile

 86 ^(e) tert-Butyl 4-(4-((1- cyanocyclobutyl)amino)phenyl)piperazine-1- carboxylate

 87 ^(e) 1-((4-((2-(Pyridin-4- yl)ethyl)sulfonyl)phenyl)amino)cyclobutanecarbonitrile

 88 ^(e) 1-((4-((Methyl(pyridin-4- ylmethyl)amino)methyl)phenyl)amino)cyclobutanecarbonitrile

 89 ^(e) 1-((4-((4-Methylpiperazin-1- yl)methyl)phenyl)amino)cyclobutanecarbonitrile

 90 ^(b) 1-((4-Bromo-3- fluorophenyl)amino) cyclobutanecarbonitrile

 91 ^(c) 1-((4-(6-Methylpyridin-3- yl)phenyl)amino)cyclobutanecarbonitrile

 92 ^(c) 1-((4-(4-Methylpyridin-3- yl)phenyl)amino)cyclobutanecarbonitrile

 93 ^(c) 1-((4-(5-Methylpyridin-3- yl)phenyl)amino)cyclobutanecarbonitrile

 94 ^(c) 1-((4-(2-Methylpyridin-3- yl)phenyl)amino)cyclobutanecarbonitrile

 95 ^(a) 1-((4-(Methyl(1- methylpiperidin-4- yl)amino)phenyl)amino)cyclobutanecarbonitrile

 96 ^(c) 1-((4-(Pyrimidin-5- yl)phenyl)amino) cyclobutanecarbonitrile

 97 ^(c) 1-((4-(5-Fluoropyridin-3- yl)phenyl)amino)cyclobutanecarbonitrile

 98 ^(c) 4-((1- (Cyanocyclobutyl)amino)- N,2-dimethylbenzamide

 99 ^(c) 4-((1-Cyanocyclobutyl) amino)-2-methoxy-N- methylbenzamide

100 ^(c) 2-Chloro-4- ((1-cyanocyclobutyl)amino)- N-methylbenzamide

101 ^(c) 1-((4-(Tetrahydro-2H-pyran-4- yl)phenyl)amino)cyclobutanecarbonitrile

102 ^(c) 4-((1-Cyanocyclobutyl) amino)-N-methyl-2-(trifluoromethyl)benzamide

103 ^(c) 4-((1-Cyanocyclopentyl) amino)-2-fluoro-N- methylbenzamide

104 ^(c) 1-((1-Oxoisoindolin-5- yl)amino) cyclobutanecarbonitrile

105 ^(e) 1-((4-(Furan-2- yl)phenyl)amino) cyclobutanecarbonitrile

106 ^(e) 1-((4-(5-Methylfuran-2- yl)phenyl)amino)cyclobutanecarbonitrile

107 ^(a) 1-((4- Hydroxyphenyl)amino) cyclobutanecarbonitrile

^(a) Aminonitrile synthesis method A, ^(b) Aminonitrile synthesis methodB, ^(c) Aminonitrile synthesis method C, ^(d) Aminonitrile synthesismethod D, ^(e) Aminonitrile synthesis method E.

Intermediate 108 4-((4,4,5,5,5-Pentafluoropentyl)thio)butan-1-ol Step 1:4-(Benzyloxy)butyl methanesulfonate

Methanesulfonyl chloride (1 mL, 13.3 mmol) was added to a cooled (0° C.)solution of 4-(benzyloxy)butan-1-ol (2 g, 11.1 mmol) and triethylamine(1.9 mL, 13.3 mmol) in DCM (20 mL) and it was stirred at 0° C. for 1 h.HCl (1M) was added to the reaction mixture and the aqueous layer wasextracted with DCM (2×). The organics were combined, dried over sodiumsulfate, and evaporated to dryness to afford 4-(benzyloxy)butylmethanesulfonate as a yellow oil. LCMS [M+1]⁺259.5.

Step 2: 4,4,5,5,5-Pentafluoropentyl 4-methylbenzenesulfonate

A mixture of 4,4,5,5,5-pentafluoropentan-1-ol (1 g, 5.6 mmol),p-toluenesulfonylchloride (1.3 g, 6.8 mmol), and triethylamine (1.2 mL,8.4 mmol) in DCM (20 mL) was stirred at room temperature for 18h. Waterwas added to the reaction mixture, the two layers were separated, andthe aqueous layer was extracted with DCM (2×). The organics werecombined, dried over sodium sulfate, and evaporated to dryness. Theresidue was purified by column chromatography on silica gel eluting with0 to 20% EtOAc/hexanes to afford 1.7 g of 4,4,5,5,5-pentafluoropentyl4-methylbenzenesulfonate as a colorless oil.

Step 3: 2-(4,4,5,5,5-Pentafluoropentyl)isothiouronium4-methylbenzenesulfonate

A mixture of 4,4,5,5,5-pentafluoropentyl 4-methylbenzenesulfonate (1.7g, 5.1 mmol) and thiourea (430 mg, 5.6 mmol) in ethanol (20 mL) wasrefluxed for 18h. The mixture was cooled to room temperature and most ofthe ethanol was removed in vacuo. Hexanes and Et₂O were added until awhite precipitate started to form and the mixture was allowed to sit atroom temperature for 30 min. The white solid was filtered, washed withhexanes, and dried to afford 1.7 g of2-(4,4,5,5,5-pentafluoropentyl)isothiouronium 4-methylbenzenesulfonateas a white solid. LCMS [M+1]⁺237.4.

Step 4: (4-(Benzyloxy)butyl)(4,4,5,5,5-pentafluoropentyl)sulfane

A mixture of 4-(benzyloxy)butyl methanesulfonate (759 mg, 2.9 mmol),2-(4,4,5,5,5-pentafluoropentyl)isothiouronium 4-methylbenzenesulfonate(1.2 g, 2.9 mmol), NaOH (5M, 5 mL) in DMF (20 mL) was stirred at roomtemperature for 4 h. EtOAc was added to the reaction mixture and theorganic layer was washed with brine (2×), dried over sodium sulfate, andevaporated to dryness. The residue was purified by column chromatographyon silica gel eluting with 0 to 20% EtOAc/hexanes to afford 960 mg of(4-(benzyloxy)butyl)(4,4,5,5,5-pentafluoropentyl)sulfane as a yellowoil. LCMS [M+1]⁺357.5.

Step 5: 4-((4,4,5,5,5-Pentafluoropentyl)thio)butan-1-ol

BBr₃ (1M in DCM, 2.9 mL, 2.9 mmol) was added dropwise to a solution of(4-(benzyloxy)butyl)(4,4,5,5,5-pentafluoropentyl)sulfane (340 mg, 0.95mmol) in DCM (5 mL) cooled to −78° C. The temperature was allowed towarm up to room temperature and the mixture was stirred for 18h. Waterwas slowly added and the reaction mixture was stirred for 10 min. Thetwo layers were separated and the aqueous layer was extracted with DCM(3×). The organics were combined, dried over sodium sulfate, andevaporated to dryness. The residue was purified by column chromatographyon silica gel eluting with 50 to 100% EtOAc/hexanes to afford 171 mg of4-((4,4,5,5,5-pentafluoropentyl)thio)butan-1-ol as a colorless oil.

Intermediate 109 4-((4,4,5,5,5-Pentafluoropentyl)sulfinyl)butan-1-ol

m-CPBA (64 mg, 0.37 mmol) was added to a cooled (0° C.) solution of4-((4,4,5,5,5-pentafluoropentyl)thio)butan-1-ol (76 mg, 0.28 mmol) inDCM (3 mL) and it was stirred at 0° C. for 30 min. The reaction mixturewas warmed to room temperature and was partitioned between a saturatedsolution of sodium bicarbonate and DCM. The organic layer was dried oversodium sulfate, and evaporated to dryness. The residue was purified bycolumn chromatography on silica gel eluting with 0 to 10% MeOH/DCM toafford 52 mg of 4-((4,4,5,5,5-pentafluoropentyl)sulfinyl)butan-1-ol as awhite solid.

Intermediate 110 5-Amino-3-(difluoromethyl)picolinonitrile Step 1:(5-Bromo-2-chloropyridin-3-yl)methanol

To a mixture of NaBH₄ (5.8 g, 152.6 mmol, 4 eq) and anhydrous CaCl₂(16.9 g, 152.6 mmol) in dry DCM (100 mL) at 0° C., was added slowlymethyl 5-bromo-2-chloronicotinate (9.5 g, 38.15 mmol). The resultingmixture was stirred at room temperature for 12h. Water was added to thereaction mixture at 0° C. The organic layer was separated, dried oversodium sulfate, and concentrated in vacuo, to afford 6.8 g (crude) of(5-bromo-2-chloropyridin-3-yl)methanol, which was used in the next stepwithout further purification. LCMS [M+H]⁺ 223.1.

Step 2: 5-Bromo-2-chloronicotinaldehyde

To a solution of (5-bromo-2-chloropyridin-3-yl)methanol (6.8 g, 30.6mmol) in DCM (200 mL), was added Dess-Martin periodinane (32.4 g, 76.6mmol) at 0° C. The resulting mixture was stirred at room temperature for12h. The reaction mixture was concentrated in vacuo and the residue waspurified by column chromatography on silica gel (0 to 30% EtOAc inpetroleum ether) to afford 5.05 g of 5-bromo-2-chloronicotinaldehyde.LCMS [M+H]⁺ 221.1.

Step 3: 5-Bromo-2-chloro-3-(difluoromethyl)pyridine

To a solution of 5-bromo-2-chloronicotinaldehyde (5.05 g, 23.2 mmol) inDCM (30 mL), were added ethanol (0.13 mL, 2.32 mmol) and DAST (7.51 g,46.4 mmol) at room temperature. The resulting mixture was stirred for 2hat that temperature. To the reaction mixture was slowly added saturatedaqueous sodium bicarbonate (100 mL). The organic layer was separated,dried over sodium sulfate, and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (0 to 50% EtOAc inpetroleum ether) to afford 3.80 g of5-bromo-2-chloro-3-(difluoromethyl)pyridine. LCMS [M+H]⁺ 243.1.

Step 4: 5-Amino-3-(difluoromethyl)picolinonitrile

The title compound was synthesized as described in Intermediate 1 (Steps3-5) using 5-bromo-2-chloro-3-(difluoromethyl)pyridine as the startingmaterial. ¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (d, 1H), 7.28-7.01 (m, 2H),6.80 (s, 2H). LCMS [M+H]⁺ 170.1.

Example 1 Synthesis of Compound 1 (Thiohydantoin Synthesis Method A)5-(5-(3-Fluoro-4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

Thiophosgene (1.3 mL, 16.04 mmol) was added to a mixture of5-amino-3-(trifluoromethyl) picolinonitrile (Intermediate 1, 3 g, 16.0mmol) and 1-((3-fluoro-4-hydroxyphenyl)amino)cyclobutane-carbonitrile(Intermediate 19, 3.3 g, 16.0 mmol) in DMA (40 mL) and the mixture washeated to 60° C. for 18h. MeOH (60 mL) and HCl (2M, 40 mL) were addedand the mixture was refluxed for 2h. The mixture was cooled to roomtemperature and slowly poured into an ice/water bath. The brown solidwas filtered, washed with water, dried, and purified by columnchromatography on silica gel eluting with 0 to 50% EtOAc/hexanes toafford 3 g of5-(5-(3-fluoro-4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrileas a beige solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.44 (s, 1H), 9.21 (d,1H), 8.74 (d, 1H), 7.27-7.05 (m, 3H), 2.64-2.42 (m, 4H), 2.01-1.91 (m,1H), 1.61-1.54 (m, 1H).

Example 2 Synthesis of Compound 2 (Thiohydantoin Synthesis Method B)5-(4-Hydroxyphenyl)-6-thioxo-7-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-5,7-diazaspiro[3.4]octan-8-one

A mixture of6-isothiocyanato-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine(Intermediate 8, 545 mg, 2.22 mmol) and1-((4-hydroxyphenyl)amino)cyclobutanecarbonitrile (Intermediate 25, 418mg, 2.22 mmol) in DMA (15 mL) was heated to 60° C. for 2h. MeOH (10 mL)and HCl (2M, 10 mL) were added and the mixture was refluxed for 1h. Themixture was cooled to room temperature and slowly poured into anice/water bath. The dark brown solid was filtered, washed with water,dried, and purified by reverse phase HPLC (Acetonitrile/water:TFA) toafford5-(4-hydroxyphenyl)-6-thioxo-7-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-5,7-diazaspiro[3.4]octan-8-oneas a light brown solid. LCMS [M+1]⁺435.4.

Example 3 Synthesis of Compound Ethyl4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoate

A mixture of thiophosgene (0.55 mL, 5.35 mmol),5-amino-3-(trifluoromethyl)picolinonitrile (Intermediate 1, 1 g, 5.35mmol), and ethyl 4-((1-cyanocyclobutyl)amino)-2-fluorobenzoate(Intermediate 20, 1.4 g, 5.35 mmol) in DMA (25 mL) was heated to 70° C.overnight. MeOH (20 mL) and HCl (2M, 20 mL) were added and the mixturewas refluxed for 2h then cooled to room temperature. Water/ice was addedand the aqueous layer was extracted with DCM (4×). The organics werecombined, dried over sodium sulfate, and evaporated to dryness. Theresidue was purified by column chromatography on silica gel eluting with0 to 50% EtOAc/hexanes to afford 1 g of ethyl4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoateas a yellow foam. ¹H NMR (300 MHz, DMSO-d₆) δ 9.21 (s, 1H), 8.74 (s,1H), 8.13 (m, 1H), 7.53 (d, 1H), 7.45 (d, 1H), 4.37 (q, 2H), 2.65-2.62(m, 2H), 2.56-2.45 (m, 2H), 2.05-1.91 (m, 1H), 1.61-1.57 (m, 1H), 1.34(t, 3H).

Example 4 Synthesis of Compound 45-(5-(4-Bromo-3-fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

Thiophosgene (0.36 mL, 4.67 mmol) was added dropwise to a solution of5-amino-3-(trifluoromethyl)picolinonitrile (Intermediate 1, 795 mg, 4.25mmol) and 1-((4-bromo-3-fluorophenyl)amino)cyclobutanecarbonitrile(Intermediate 90, 1.14 g, 4.25 mmol) in DMA (30 mL). The resultingmixture was heated to 60° C. overnight. MeOH (8 mL) and HCl (2M, 8 mL)were added and the mixture was refluxed for 2h then cooled to roomtemperature. Water was slowly added until a light brown solidprecipitated. The solid was filtered, washed with water, dried,dissolved in MeOH, and absorbed on silica gel. Purification by columnchromatography on silica gel eluting with 10% EtOAc/hexanes afforded 616mg of5-(5-(4-bromo-3-fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrileas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.21 (d, 1H), 8.74 (d,1H), 8.00 (t, 1H), 7.55 (dd, 1H), 7.28 (dd, 1H), 2.67-2.59 (m, 2H),2.55-2.45 (m, 2H), 1.99-1.95 (m, 1H), 1.61-1.56 (m, 1H).

Example 5 Synthesis of Compound 54-(7-(6-Cyano-5-methylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenzamide

A mixture of 5-isothiocyanato-3-methylpicolinonitrile (Intermediate 6,2.9 g, 16.57 mmol) and4-((1-cyanocyclobutyl)amino)-2-fluoro-N-methylbenzamide (Intermediate21, 2.7 g, 11.05 mmol) in DMA was heated to 65° C. overnight. MeOH (50mL) and HCl (2M, 70 mL) were added and the mixture was heated to 105° C.for 1h then cooled to room temperature. Water was slowly added until ayellow solid precipitated and the mixture was stirred at roomtemperature for 3h. The solid was filtered, washed with water, dissolvedin DCM, dried over sodium sulfate, and absorbed on silica gel.Purification by column chromatography on silica gel eluting with 0 to100% EtOAc/hexanes afforded a pale yellow solid. This solid wastriturated in MeOH, filtered, and dried to afford 1.39 g (29%) of4-(7-(6-cyano-5-methylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenzamideas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.64 (d, 1H), 8.40 (m,1H), 8.06 (d, 1H), 7.75 (t, 1H), 7.43 (dd, 1H), 7.32 (dd, 1H), 2.73 (d,3H), 2.59-2.53 (m, 2H), 2.52 (s, 3H), 2.44-2.23 (m, 2H), 1.91-1.88 (m,1H), 1.52-1.48 (m, 1H). LCMS [M+1]⁺424.0.

Example 6 Synthesis of Compound 64-(3-(6-Cyano-5-methylpyridin-3-yl)-4-oxo-2-thioxo-1,3-diazaspiro[4.4]nonan-1-yl)-2-fluoro-N-methylbenzamide

Thiophosgene (0.35 mL) was added dropwise to a solution of4-((1-cyanocyclopentyl)amino)-2-fluoro-N-methylbenzamide (Intermediate103, 400 mg, 1.53 mmol) and 5-amino-3-methylpicolinonitrile(Intermediate 2, 303 mg, 2.28 mmol) in DMA (30 mL) under N₂ atmosphere.The resulting mixture was stirred at 60° C. overnight. MeOH (22 mL) andHCl (2M, 11 mL) were added and the mixture was refluxed for 2 h thencooled to room temperature. The reaction mixture was poured into water(75 mL) and extracted with EtOAc. The organic layer was dried oversodium sulfate and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (1:5 EtOAc/petroleum ether), toafford 300 mg of4-(3-(6-cyano-5-methylpyridin-3-yl)-4-oxo-2-thioxo-1,3-diazaspiro[4.4]nonan-1-yl)-2-fluoro-N-methylbenzamideas a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.74 (s, 1H), 8.47(m, 1H), 8.17 (s, 1H), 7.78 (m, 1H), 7.55 (d, 1H), 7.41 (d, 1H), 2.81(d, 3H), 2.60 (s, 3H), 2.29-2.21 (m, 4H), 1.72 (m, 2H), 1.41 (m, 2H).LCMS [M+1]⁺438.1.

Example 7 Synthesis of Compound 73-Methyl-5-(5-(4-(5-methylfuran-2-yl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)picolinonitrile

Thiophosgene (0.1 mL) was added dropwise to a solution of1-((4-(5-methylfuran-2-yl)phenyl)amino)cyclobutanecarbonitrile(Intermediate 106, 280 mg, 1.11 mmol) and5-amino-3-methylpicolinonitrile (Intermediate 2, 177 mg, 1.33 mmol) inDMA (20 mL). The resulting mixture was stirred at 60° C. overnight. MeOH(16 mL) and HCl (2M, 8 mL) were added and the mixture was refluxed for 2h then cooled to room temperature. The reaction mixture was poured intowater (200 mL) and extracted with EtOAc. The organic layer was washedwith brine, dried over Sodium sulfate and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel (1:3EtOAc/petroleum ether), to afford 140 mg of3-methyl-5-(5-(4-(5-methylfuran-2-yl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)picolinonitrile.¹HNMR (400 MHz, DMSO-d₆) δ 8.74 (s, 1H), 8.16 (s, 1H), 7.86 (d, 2H),7.46 (d, 2H), 6.98 (d, 1H), 6.28 (d, 1H), 2.63 (m, 2H), 2.60 (s, 3H),2.51-2.43 (m, 2H), 2.38 (s, 3H), 1.97 (m, 1H), 1.57 (m, 1H). LCMS[M+1]⁺429.1.

Compounds 8 to 117 were synthesized from the appropriate amines (amineswere either commercially available, synthesized in the Intermediatessection, or synthesized from literature procedures) and aminocyanohydrins, according to the conditions indicated (see footnotes):8^(a), 9^(a), 10^(a), 11^(a), 12^(a), 13^(a), 14^(a), 15^(a), 16^(b),17^(b), 18^(b), 19^(a), 20^(a), 21^(a), 22^(a), 23^(a), 24^(b), 25^(b),26^(b), 27^(b), 28^(b), 29^(a), 30^(b), 31^(b), 32^(a), 33^(a), 34^(b),35^(b), 36^(b), 37^(b), 38^(a), 39^(b), 40^(b), 41^(b), 42^(a), 43^(a),44^(b), 45^(b), 46^(a), 47^(b), 48^(b), 49^(b), 50^(b), 51^(b), 52^(b),53^(b), 54^(b), 55^(b), 56^(a), 57^(b), 58^(b), 59^(b), 60^(b), 61^(b),62^(b), 63^(a), 64^(a), 65^(b), 66^(b), 67^(a), 68^(a), 69^(a), 70^(a),71^(a), 72^(a), 73^(a), 74^(a), 75^(a), 76^(a), 77^(a), 78^(a), 79^(a),80^(b), 81^(b), 82^(b), 83^(b), 84^(b), 85^(b), 86^(a), 87^(a), 88^(a),89^(b), 90^(b), 91^(b), 92^(b), 93^(b), 94^(a), 95^(a), 96^(a), 97^(a),98^(a), 99^(a), 100^(a), 101^(a), 102^(a), 103^(a), 104^(a), 105^(a),106^(a), 107^(a), 108^(a), 109^(b), 110^(a), 111^(b), 112^(a), 113^(a),114^(a), 115^(a), 116^(b), 117^(b). ^(a)Thiohydantoin synthesis methodA. ^(b)Thiohydantoin synthesis method B.

Example 8 Synthesis of Compound 1185-(8-Oxo-5-(4-(piperazin-1-yl)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

A mixture of tert-butyl4-(4-(1-cyanocyclobutylamino)phenyl)piperazine-1-carboxylate(Intermediate 86, 0.25 g, 0.70 mmol) and5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (Intermediate 10,241 mg, 1.05 mmol) in DMA (5 mL) was heated to 80° C. for 12h. 2MHCl/MeOH=1/1 (10 mL) was added then and the resulting mixture was heatedat 100° C. for 2h. The reaction mixture was cooled to room temperatureand diluted with EtOAc. The organic layer was washed with water (3×),dried over sodium sulfate, and concentrated in vacuo. The residue waspurified by Prep-HPLC (20% acetonitrile in water) to afford 75 mg of5-(8-oxo-5-(4-(piperazin-1-yl)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile.¹H NMR (DMSO-d₆, 300 MHz) δ 9.26 (s, 1H), 9.19 (m, 1H), 8.74 (m, 1H),7.25 (d, 2H), 7.15 (d, 2H), 3.48 (m, 4H), 3.22 (m, 4H), 2.60-2.49 (m,2H), 2.48-2.40 (m, 2H), 1.95 (m, 1H), 1.63 (m, 1H). LCMS [M+H]⁺ 487.1.

Example 9 Synthesis of Compound 119 tert-Butyl4-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)piperazine-1-carboxylate

To a solution of5-(8-oxo-5-(4-(piperazin-1-yl)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile(15 mg, 0.031 mmol) in dry DCM (2 mL) was added TEA (6 μl, 0.062 mmol)and (Boc)₂O (10 mg, 0.046 mmol). The mixture was stirred at roomtemperature for 3h and then concentrated. The residue was purified bycolumn chromatography on silica gel (0 to 20% EtOAc in petroleum ether)to afford 10 mg of tert-butyl4-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)piperazine-1-carboxylate.¹H NMR (CDCl₃, 300 MHz) δ 9.10 (d, 1H), 8.36 (d, 1H), 7.18 (d, 2H), 7.04(d, 2H), 3.60 (m, 4H), 3.27 (m, 4H), 2.63-2.60 (m, 4H), 2.24-1.97 (m,1H), 1.71-1.63 (m, 1H), 1.49 (s, 9H).

Example 10 Synthesis of Compound 1204-(7-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-N-methylbenzenesulfonamide

A mixture of4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro-[3.4]octan-5-yl)benzenesulfonamide(Compound 81, 97 mg, 0.20 mmol), methyl tosylate (37 mg, 0.20 mmol), andCs₂CO₃ (65 mg, 0.20 mmol) in acetonitrile (1 mL) was heated at 50° C.for 20h in a sealed tube. After being cooled room temperature, thereaction mixture was diluted with water and extracted with EtOAc (3×).The organic layer was dried over magnesium sulfate and concentrated togive a residue that was purified by column chromatography on silica gel(hexanes:DCM:acetone=5:9:1) to afford 30 mg of4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]-octan-5-yl)-N-methylbenzenesulfonamideas a white solid. ¹H NMR (400 MHz, CDCl₃) δ 9.11 (s, 1H), 8.37 (s, 1H),8.10 (dd, 2H), 7.58-7.49 (m, 2H), 4.52 (d, 1H), 2.80 (m, 3H), 2.78-2.69(m, 2H), 2.63-2.47 (m, 2H), 2.29 (m, 1H), 1.74 (m, 1H). LCMS[M+1+Na]⁺518.0.

Example 11 Synthesis of Compound 1214-(7-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-N,N-dimethylbenzenesulfonamide

The title compound was obtained as a side product from the proceduredescribed for Example 10. ¹H NMR (400 MHz, CDCl₃) δ 9.11 (s, 1H), 8.37(s, 1H), 8.02 (dd, 2H), 7.52 (dd, 2H), 2.84 (s, 6H), 2.83-2.68 (m, 2H),2.55 (m, 2H), 2.37-2.21 (m, 1H), 1.80-1.64 (m, 1H). LCMS [M+Na]⁺532.0.

Example 12 Synthesis of Compound 122 Methyl4-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)butanoate

A mixture of 5-isothiocyanato-3-trifluoromethylpyridine-2-carbonitrile(Intermediate 10, 582 mg, 2.54 mmol) and4-(4-(1-cyanocyclobutylamino)phenyl)butanoic acid (Intermediate 80, 410mg, 1.59 mmol) in DMF (3 mL) was stirred at room temperature overnight.To this mixture were added methanol (4 mL) and HCl (2M, 2 mL) and theresulting mixture was refluxed for 3 h. After being cooled roomtemperature, the reaction mixture was poured into cold water andextracted with EtOAc (3×). The organic layers were dried over magnesiumsulfate and concentrated to dryness. Column chromatography of theresidue on silica gel (Hexane:EtOAc=4:1) afforded 256 mg of methyl4-(4-(7-(6-cyano-5-(trifluoromethyl)-pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)butanoateas a white solid. ¹H NMR (400 MHz, CDCl₃) δ 9.11 (d, 1H), 8.38 (d, 1H),7.42 (d, 2H), 7.36-7.19 (m, 2H), 3.70 (s, 3H), 2.87-2.75 (m, 2H),2.75-2.53 (m, 4H), 2.42 (t, 2H), 2.26 (m, 1H), 2.05 (m, 2H), 1.78-1.61(m, 1H). LCMS [M+1]⁺503.0.

Example 13 Synthesis of Compound 1235-(5-(4-Fluoro-3-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

Trimethylsilyl iodide (7.0 ml, 51.1 mmol) was added to a solution of5-(5-(4-fluoro-3-methoxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile(Compound 32, 3 g, 5.1 mmol) in acetonitrile (50 mL) and the mixture wasrefluxed for 24 h. The mixture was cooled to room temperature, pouredinto water, and extracted with EtOAc (3×). The organics were combined,washed with sat′d solution of NaHSO₃, dried over MgSO₄, and evaporatedto dryness. The residue was purified by column chromatography on silicagel eluting with EtOAc/Hexane=1/5 to afford 1.1 g of5-(5-(4-fluoro-3-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile.¹H NMR (400 MHz, CDCl₃) δ 9.10 (d, 1H), 8.38 (d, 1H), 7.27-7.22 (m, 1H),6.93 (dd, 1H), 6.78 (m, 1H), 2.74-2.55 (m, 1H), 2.23 (m, 1H), 1.80-1.59(m, 4H).

Example 14 Synthesis of Compound 1245-(5-(4-(3-(4-Methylpiperazin-1-yl)propyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

A solution of5-(5-(4-(3-hydroxypropyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile(Compound 86, 66 mg, 0.14 mmol) and methanesulfonyl chloride (0.033 mL,0.42 mmol) in DCM (2 mL) was stirred at room temperature for 2h. Thesolution was washed with water (2×) and brine, dried over magnesiumsulfate and concentrated to give 80 mg of the corresponding mesylatewithout purification. The mesylate (45 mg, 0.084 mmol), methylpiperazine (0.02 mL, 0.17 mmol) and triethylamine (0.04 mL, 0.25 mmol)in dichloromethane was stirred at room temperature overnight, then atreflux for 16h. The mixture was partitioned between water and DCM andthe aqueous was further extracted with DCM (2×). The combined organicswere washed with brine, dried (MgSO₄) and concentrated. Purification bysilica gel chromatography (0 to 80% EtOAc/hexanes) afforded 20 mg of5-(5-(4-(3-(4-methylpiperazin-1-yl)propyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrileas a beige solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.23 (d, 1H), 8.77 (d,1H), 7.45 (d, 2H), 7.31 (d, 2H), 2.76-2.57 (m, 4H), 2.49-2.23 (m, 5H),2.14 (s, 3H), 2.02-1.89 (m, 1H), 1.85-1.73 (m, 3H), 1.59-1.46 (m, 1H).LCMS [M+1]⁺543.1.

Example 15 Synthesis of Compound 1255-(5-(Benzo[d]oxazol-6-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrileStep 1:5-(5-(4-Amino-3-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

A mixture of 5-amino-3-(trifluoromethyl)picolinonitrile (Intermediate 1,110 mg, 0.59 mmol), benzo[d]oxazol-6-amine (Intermediate 79, 125 mg,0.59 mmol), and thiophosgene (0.05 mL, 0.60 mmol) in anhydrous DMA (3mL) was stirred at 60° C. for 16h. Methanol (3 mL) and 2M HCl (1.5 mL)were then added and the mixture was heated at 90° C. for 2h. Thereaction mixture was cooled and poured into ice/water (40 mL) and theresultant solid was filtered to afford 150 mg of5-(5-(4-amino-3-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrileas a brown powder. LCMS [M+1]⁺434.0.

Step 2:5-(5-(Benzo[d]oxazol-6-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

A mixture of5-(5-(4-amino-3-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile(60 mg, 0.14 mmol) and triethylorthoformate (0.050 mL, 0.28 mmol) inanhydrous DMF (1 mL) was heated at 100° C., 1h. The mixture was dilutedwith water, extracted with EtOAc (3×), the organics combined and washedwith water (2×), brine, dried (MgSO₄) and concentrated. Purification bycolumn chromatography, eluting with 30% EtOAc/hexanes provided 23 mg of5-(5-(benzo[d]oxazol-6-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrileas a pale yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.24 (d, 1H), 8.95(s, 1H), 8.78 (d, 1H), 8.05 (d, 1H), 7.94 (d, 1H), 7.45 (dd, 1H),2.74-2.61 (m, 2H), 2.59-2.47 (m, 2H), 2.03-1.90 (m, 1H), 1.61-1.48 (m,1H). LCMS [M+1]⁺444.0.

Example 16 Synthesis of Compound 1265-(5-(3-Fluoro-4-(2-(1-methyl-1H-pyrazol-5-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

A mixture of5-(5-(3-fluoro-4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile(Compound 1, 100 mg, 0.23 mmol), 2-(1-methyl-1H-pyrazol-5-yl)ethanol(43.5 mg, 0.34 mmol), triphenylphosphine (89 mg, 0.34 mmol), anddiisopropyl azodicarboxylate (0.07 mL, 0.34 mmol) in THF (5 mL) wasstirred at room temperature for 18h. The reaction mixture was absorbedon silica gel and purified by column chromatography on silica geleluting with EtOAc/hexanes to afford impure desired product that wasrepurified by reverse phase HPLC (acetonitrile/water:TFA). The fractionscontaining the desired compound were combined, acetonitrile was removedin vacuo, and the remaining aqueous layer was treated with a saturatedsolution of sodium bicarbonate. The aqueous layer was extracted with DCM(3×), the organics were combined, dried over sodium sulfate, andevaporated to dryness to afford 29 mg of5-(5-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-5-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile as a beige solid. LCMS [M+1]⁺545.5.

Example 17 Synthesis of Compound 1275-(5-(3-Fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

A mixture of5-(5-(3-fluoro-4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile(Compound 1, 100 mg, 0.23 mmol), 2-(pyrrolidin-1-yl)ethanol (35μL, 0.30mmol), triphenylphosphine (79 mg, 0.30 mmol), and diisopropylazodicarboxylate (60 μL, 0.30 mmol) in THF (5 mL) was stirred at roomtemperature for 2 days. The reaction mixture was absorbed on silica geland purified by column chromatography on silica gel eluting with 0 to10% MeOH/DCM to afford impure desired product that was repurified byreverse phase HPLC (acetonitrile/water, 0.1% TFA). The fractionscontaining the desired compound were combined, acetonitrile was removedin vacuo, and the remaining aqueous layer was treated with a saturatedsolution of sodium bicarbonate. The aqueous layer was extracted with DCM(3×), the organics were combined, dried over sodium sulfate, andevaporated to dryness to afford 30 mg of5-(5-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrileas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.21 (d, 1H), 8.74 (d,1H), 7.40 (t, 1H), 7.35 (dd, 1H), 7.22 (d, 1H), 4.24 (t, 2H), 2.86 (t,2H), 2.65-2.42 (m, 8H), 1.98-1.95 (m, 1H), 1.70 (m, 4H), 1.60-1.54 (m,1H). LCMS [M+1]⁺534.9.

Example 18 Synthesis of Compound 1285-(5-(4-(Benzyloxy)-3-fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

A mixture of5-(5-(3-fluoro-4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile(Example 1, 100 mg, 0.23 mmol), benzyl alcohol (35 μL, 0.30 mmol)triphenylphosphine (79 mg, 0.30 mmol), and diisopropyl azodicarboxylate(60 μL, 0.30 mmol) in THF (5 mL) was stirred at room temperature for 2days then heated to 60° C. overnight. The reaction mixture was absorbedon silica gel and purified by column chromatography on silica geleluting with 0 to 50% EtOAc/Hexanes to afford impure desired product.The solid was triturated in MeOH, filtered, and dried to afford 36 mg of5-(5-(4-(benzyloxy)-3-fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrileas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.21 (d, 1H), 8.75 (d,1H), 7.53-7.36 (m, 7H), 7.23 (d, 1H), 5.28 (s, 2H), 2.66-2.60 (m, 2H),2.53-2.43 (m, 2H), 2.02-1.92 (m, 1H), 1.61-1.55 (m, 1H).

Example 19 Synthesis of Compound 1295-(5-(4-((1-Methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

To a solution of5-(5-(4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile(Compound 63, 150 mg, 0.36 mmol), 1-methylpiperidin-4-ol (50 μL, 0.39mmol), and triphenylphosphine (125 mg, 0.47 mmol) in anhydrous THF (2mL) was added diisopropyl azodicarboxylate (0.1 mL, 0.47 mmol) and thereaction mixture was stirred at room temperature overnight. Additional1-methylpiperidin-4-ol (50 μL, 0.39 mmol), triphenylphosphine (125 mg,0.47 mmol) and diisopropyl azodicarboxylate (0.1 mL, 0.47 mmol) wasadded and the reaction was allowed to stir an additional 16h. Themixture was partitioned between EtOAc and water and the aqueous layerwas extracted with EtOAc (2×).

The combined organics were washed with water and brine, then dried overmagnesium sulfate and concentrated in vacuo. Purification by silica gelchromatography (0 to 80% EtOAc/hexanes, then 0 to 5%MeOH/dichloromethane) gave impure product which was further purified bypreparative HPLC (40 to 75% acetonitrile/water, 0.1% TFA) to afford 45mg of5-(5-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrileas a pale yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.22 (d, 1H), 8.76(d, 1H), 7.30 (d, 2H), 7.15 (d, 2H), 4.52-4.39 (m, 1H), 2.72-2.56 (m,4H), 2.49-2.38 (m, 2H), 2.25-2.14 (m, 5H), 2.03-1.90 (m, 3H), 1.77-1.49(m, 3H). LCMS [M+1]⁺516.0.

Compounds 130 to 201 were synthesized following the procedure describedin Example 16 from the appropriate phenols and alcohols (phenols andalcohols were either commercially available, synthesized in theIntermediates section, or synthesized from published procedures).

Example 20 Synthesis of Compound 2025-(5-(4-(2-(4-Acetylpiperazin-1-yl)ethoxy)-3-fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

A mixture of5-(5-(3-fluoro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile(Compound 174, 50 mg, 0.1 mmol), acetic anhydride (13 μL, 0.14 mmol),and triethylamine (40 μL, 0.27 mmol) in DCM (2 mL) was stirred at roomtemperature for 2 days. The reaction mixture was absorbed on silica geland purified by column chromatography on silica gel eluting with 0 to10% MeOH/DCM to afford 34 mg of5-(5-(4-(2-(4-acetylpiperazin-1-yl)ethoxy)-3-fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrileas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.21 (s, 1H), 8.74 (s,1H), 7.42 (t, 1H), 7.35 (dd, 1H), 7.22 (m, 1H), 4.28 (t, 2H), 3.42 (m,4H), 2.80 (t, 2H), 2.65-2.59 (m, 2H), 2.54-2.44 (m, 6H), 1.98 (m, 4H),1.57 (m, 1H). LCMS [M+1]⁺591.9.

Example 21 Synthesis of Compound 2035-(5-(3-Fluoro-4-methoxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

A mixture of5-(5-(3-fluoro-4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile(Compound 1, 100 mg, 0.23 mmol), methyl iodide (0.14 mL, 0.23 mmol), andpotassium carbonate (31 mg, 0.23 mmol) in acetone (4 mL) was stirred atroom temperature for 4h. Excess potassium carbonate was removed and thereaction mixture was absorbed on silica gel and purified by columnchromatography on silica gel eluting with 0 to 30% EtOAc/hexanes toafford 74 mg of5-(5-(3-fluoro-4-methoxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrileas a white solid. LCMS [M+1]⁺451.4

Compounds 204 and 205 were synthesized following the procedure describedin Example 21 from the appropriate phenols.

Example 22 Synthesis of Compound 2065-(8-Oxo-5-(4-(pyrimidin-2-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

A mixture of5-(5-(4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile(Compound 63, 50 mg, 0.12 mmol), 2-chloropyrimidine (17 mg, 0.15 mmol),and cesium carbonate (60 mg, 0.18 mmol) in anhydrous THF (1.2 mL) washeated at reflux overnight. The reaction mixture was cooled to roomtemperature and water was added.

The aqueous was extracted with EtOAc (3×), the organics combined andwashed with brine, dried (MgSO₄) and concentrated. Purification bycolumn chromatography on silica gel eluting with 0 to 60% EtOAc/hexanesprovided 30 mg of5-(8-oxo-5-(4-(pyrimidin-2-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrileas an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.24 (d, 1H), 8.78(d, 1H), 8.73 (d, 2H), 7.48 (dd, 4H), 7.35 (t, 1H), 2.72-2.61 (m, 2H),2.54-2.42 (m, 2H), 2.10-1.93 (m, 1H), 1.69-1.52 (m, 1H). LCMS[M+1]⁺497.8.

Example 23 Synthesis of Compound 2075-(8-Oxo-5-(4-(pyrazin-2-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

A mixture of5-(5-(4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile(Compound 63, 100 mg, 0.24 mmol), NaH (14 mg, 0.36 mmol, 60% dispersionin oil) and chloropyrazine (0.025 mL, 0.29 mmol) in anhydrous DMF (1.4mL) was heated at 90° C. for 16h. Additional chloropyrazine (0.025 mL,0.29 mmol) was added and heating was continued for 16 h. The reactionmixture was cooled to room temperature and water was added. The aqueouswas extracted with EtOAc (3×), the organics combined and washed withbrine, dried (MgSO₄) and concentrated. Purification by columnchromatography on silica gel eluting with 0 to 50% EtOAc/hexanesafforded 50 mg of impure product. Further purification by preparativeHPLC (30 to 100% acetonitrile/water, 10 min) provided 10 mg of5-(8-oxo-5-(4-(pyrazin-2-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrileas an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.23 (d, 1H), 8.78(d, 1H), 8.65 (d, 1H), 8.46 (d, 1H), 8.31 (dd, 1H), 7.48 (dd, 4H),2.75-2.60 (m, 2H), 2.57-2.42 (m, 2H), 2.06-1.94 (m, 1H), 1.68-1.53 (m,1H). LCMS [M+1]⁺496.9.

Compounds 208 and 209 were synthesized following the procedure describedin Example 23 from the appropriate phenols.

Example 24 Synthesis of Compound 2103-Methyl-5-(8-oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)picolinonitrile

Tert-butyl4-(4-(7-(6-cyano-5-methylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenoxy)piperidine-1-carboxylate(prepared by reaction of5-(5-(4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-methylpicolinonitrile(Compound 77) with tert-butyl 4-hydroxypiperidine-1-carboxylate,according to Example 16, 300 mg, 0.55 mmol) was stirred in 2MHCl/methanol (1.5 mL) at room temperature overnight. The mixture wasconcentrated and purified by column chromatography, eluting with 10%MeOH/DCM to provide 230 mg of3-methyl-5-(8-oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)picolinonitrileas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.72 (d, 1H), 8.14 (d,1H), 7.30 (d, 2H), 7.13 (d, 2H), 4.53-4.42 (m, 1H), 3.94-3.86 (m, 1H),3.02-2.83 (m, 3H), 2.66-2.50 (m, 5H), 2.49-2.33 (m, 3H), 2.11-1.80 (m,3H), 1.60-1.33 (m, 3H). LCMS [M+1]⁺448.1.

Example 25 Synthesis of Compound 2115-(8-Oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

The title compound was synthesized as described in Example 24 usingCompound 63 as the starting material. ¹H NMR (300 MHz, DMSO-d₆) δ 9.22(d, 1H), 8.75 (d, 1H), 7.29 (d, 2H), 7.16 (d, 2H), 4.48 (m, 1H), 3.32(s, 1H), 3.01-2.94 (dt, 2H), 2.64-2.57 (m, 4H), 2.51-2.38 (m, 2H),1.98-1.95 (m, 3H), 1.58-1.43 (m, 3H). LCMS [M+1]⁺502.2.

Example 26 Synthesis of Compound 2125-(8-Oxo-5-(4-((1-propionylpiperidin-4-yl)oxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

Propionyl chloride (17 μL, 0.2 mmol) was added to a mixture of5-(8-oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile(50 mg, 0.1 mmol) and triethylamine (28 μL, 0.2 mmol) in THF (2 mL) andthe resulting milky mixture was stirred at room temperature overnight.Methanol was added to quench the reaction and the mixture was absorbedon silica gel and purified by column chromatography on silica geleluting with 50 to 100% EtOAc/hexanes to afford 21 mg of5-(8-oxo-5-(4-((1-propionylpiperidin-4-yl)oxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrileas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.15 (d, 1H), 8.69 (s,1H), 7.25 (d, 2H), 7.13 (d, 2H), 4.62 (m, 1H), 3.85 (m, 1H), 3.62 (m,1H), 3.29 (m, 1H), 3.15 (m, 1H), 2.55-2.52 (m, 2H), 2.42 (m, 2H),2.39-2.25 (m, 2H), 1.92-1.88 (m, 3H), 1.50-1.45 (m, 3H), 0.93 (t, 3H).LCMS [M+1]⁺558.1.

Compounds 213 to 219 were synthesized following the procedure describedin Example 26 from the appropriate piperidines and the appropriate acidchlorides, chloroformates, alkyl bromides, or sulfonyl chlorides.

Example 27 Synthesis of Compound 2205-(5-(4-((1-Isopropylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

To a solution of5-(8-oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile(50 mg, 0.10 mmol) in anhydrous THF (1 mL) was added 2-bromopropane (20μL, 0.20 mmol) followed by cesium carbonate (100 mg, 0.30 mmol). Thereaction mixture was heated at 70° C. overnight. DMF (1 mL) was added toimprove solubility and the reaction was heated at 85° C. for 3 h. Themixture was cooled to room temperature and partitioned between water andEtOAc. The aqueous was extracted further with EtOAc (2×) and thecombined organics were washed with water, then brine. The organics weredried over magnesium sulfate, filtered and concentrated. Purification bypreparative HPLC provided 5 mg of5-(5-(4-((1-isopropylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrileas an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.04 (d, 1H), 8.30(d, 1H), 7.13 (d, 2H), 6.99 (d, 2H), 4.37-4.26 (m, 1H), 2.81-2.33 (m,10H), 2.25-1.74 (m, 5H), 1.00 (d, 6H). LCMS [M+1]⁺544.0.

Example 28 Synthesis of Compound 221 Ethyl2-(4-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenoxy)piperidin-1-yl)acetate

The title compound was synthesized as described in Example 27 using5-(8-oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrileand ethyl 2-bromoacetate as starting materials. LCMS [M+1]⁺588.1.

Example 29 Synthesis of Compound 2224-(4-(7-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenoxy)piperidine-1-carboxamide

A mixture of5-(8-oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile(70 mg, 0.14 mmol) and isocyanatotrimethylsilane (23 μL, 0.17 mmol) inDCM (3 mL) was stirred at room temperature overnight. Water was addedand the mixture was stirred vigorously for 1h. The aqueous layer wasextracted with DCM (3×), the organics were combined, dried over sodiumsulfate, and evaporated to dryness. Column chromatography on silica gel(0 to 20% MeOH/DCM) afforded 55 mg of4-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenoxy)piperidine-1-carboxamideas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.69 (s,1H), 7.23 (d, 2H), 7.12 (d, 2H), 5.92 (s, 2H), 4.53 (m, 1H), 3.67-3.63(m, 2H), 3.08-3.04 (m, 2H), 2.44 (m, 2H), 2.39 (m, 2H), 1.88 (m, 3H),1.46 (m, 3H). LCMS [M+1]⁺545.2

Example 30 Synthesis of Compound 2235-(5-(4-(2-Hydroxyethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-methylpicolinonitrile

Dihydrofuran-2,5-dione (604 mg, 6.87 mmol) in DMF (5 mL) was added to amixture of5-(5-(4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-methylpicolinonitrile(500 mg, 1.37 mmol) and potassium carbonate (378 mg, 2.74 mmol) in DMF(10 mL) and the resulting mixture was heated to 85° C. overnight. Themixture was cooled to room temperature and partitioned between water andEtOAc. The aqueous was extracted further with EtOAc (2×) and thecombined organics were washed with water, then brine. The organics weredried over sodium sulfate, filtered, and concentrated. Columnchromatography on silica gel (50 to 100% EtOAc/hexanes) afforded 396 mgof5-(5-(4-(2-hydroxyethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-methylpicolinonitrileas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.71 (d, 1H), 8.14 (d,1H), 7.33 (d, 2H), 7.13 (d, 2H), 4.92 (t, 1H), 4.11-4.05 (m, 2H),3.78-3.73 (m, 2H), 2.63-2.5 (m, 5H), 2.49-2.37 (m, 2H), 2.00-1.90 (m,1H), 1.56-1.51 (m, 1H). LCMS [M+1]⁺409.0.

Example 31 Synthesis of Compound 2244-(7-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoicacid

A mixture of ethyl4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoate(Compound 3, 1 g, 2.03 mmol) and NaOH (3M, 10 mL) in MeOH (10 mL) wasstirred at room temperature for 18h. Aqueous HCl (2M) was added to thereaction mixture until the pH=2 and the aqueous layer was extracted withDCM (5×), the organics were combined, dried over sodium sulfate, andevaporated to dryness to afford 900 mg of4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoicacid as a light yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 13.58 (s, 1H),9.22 (s, 1H), 8.75 (s, 1H), 8.13 (t, 1H), 7.51 (dd, 1H), 7.43 (dd, 1H),2.69-2.49 (m, 4H), 2.03-1.93 (m, 1H), 1.63-1.57 (m, 1H).

Compounds 225 to 228 were synthesized following the procedure describedin Example 31 from the corresponding ester.

Example 32 Synthesis of Compound 2295-(7-(6-Carbamoyl-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoicacid

The title compound was synthesized as a by-product in the synthesis ofCompound 226. ¹H NMR (300 MHz, DMSO-d₆) δ 13.63 (s, 1H), 8.95 (s, 1H),8.50 (s, 1H), 8.27 (s, 1H), 7.95 (m, 2H), 7.72 (m, 1H), 7.58 (t, 1H),2.65 (m, 2H), 2.45 (m, 2H), 1.97 (m, 1H), 1.56 (m, 1H). LCMS[M+1]⁺483.4.

Example 33 Synthesis of Compound 2304-(4-(7-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)-N-methylbutanamide

To a solution of4-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)butanoicacid (Compound 227, 85 mg, 0.17 mmol) in DCM (2 mL) were addedtriethylamine (0.013 mL, 0.09 mmol) and 4-nitrophenyl chloroformate (15mg, 0.07 mmol). The mixture was stirred at room temperature for 1h andmethylamine (0.3 mL, 2M in THF) was added. After 30 min, the mixture wasdiluted with water and extracted with EtOAc (2×). The organic layerswere dried over magnesium sulfate and concentrated. Columnchromatography on silica gel (Hexane:EtOAc=1:1) afforded 35 mg (40%) of4-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)-N-methylbutanamideas a white solid. ¹H NMR (400 MHz, CDCl₃) δ 9.11 (d, 1H), 8.38 (d, 1H),7.42 (d, 2H), 7.22 (d, 2H), 2.86-2.81 (m, 3H), 2.81-2.73 (t, 2H),2.73-2.64 (m, 2H), 2.64-2.53 (m, 2H), 2.26 (t, 2H), 2.24-2.17 (m, 1H),2.11-2.01 (m, 2H), 1.69 (m, 1H). LCMS [M+1]⁺502.0.

Example 34 Synthesis of Compound 2314-(7-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzamide

To a suspension of4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoicacid (Compound 224, 500 mg, 1.08 mmol) in DCM was added DMF (cat., 0.1mL), followed by oxalyl chloride (0.14 mL, 1.61 mmol). The mixture wasstirred at room temperature for 4h then concentrated in vacuo to producea yellow residue that was further dried on a high vacuum pump. Ammonia(0.5M in dioxane, 40 mL, 20 mmol) was directly added to the residue andthe mixture was stirred at room temperature overnight. MeOH was addedand the mixture was absorbed onto silica gel and purified by flashchromatography (50 to 100% EtOAc/Hexanes) to afford impure desiredproduct that was repurified by reverse phase HPLC(acetonitrile/water:TFA). The fractions containing the desired compoundwere combined, acetonitrile was removed in vacuo, and the remainingaqueous layer was treated with a saturated solution of sodiumbicarbonate. The aqueous layer was extracted with DCM (3×), the organicswere combined, dried over sodium sulfate, and evaporated to dryness toafford 100 mg of4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzamideas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.21 (s, 1H), 8.75 (s,1H), 7.95 (s, 1H), 7.87 (t, 1H), 7.80 (s, 1H), 7.46 (dd, 1H), 7.37 (dd,1H), 2.69-2.62 (m, 2H), 2.55-2.47 (m, 2H), 2.00 (m, 1H), 1.58 (m, 1H).

Compounds 232 and 233 were synthesized following the procedure describedin Example 34 from the appropriate carboxylic acids.

Example 35 Synthesis of Compound 2344-(7-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(2-(pyrrolidin-1-yl)ethyl)benzamide

A mixture of4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoicacid (Compound 224, 100 mg, 0.21 mmol), 2-(pyrrolidin-1-yl)ethanamine(32 mg, 0.28 mmol), HATU (106 mg, 0.28 mmol), and DIEA (0.1 mL, 0.63mmol) in DCM (3 mL) and DMF (1.5 mL) was stirred at room temperature for18 h. Brine and EtOAc were added and the aqueous layer was extractedwith EtOAc (4×), the organics were combined, dried over sodium sulfate,and evaporated to dryness. The residue was purified by columnchromatography on silica gel eluting with 0 to 10% MeOH/DCM to affordimpure desired product that was repurified by reverse phase HPLC(acetonitrile/water:TFA). The fractions containing the desired compoundwere combined, acetonitrile was removed in vacuo, and the remainingaqueous layer was treated with a saturated solution of sodiumbicarbonate. The aqueous layer was extracted with DCM (3×), the organicswere combined, dried over sodium sulfate, and evaporated to dryness toafford 88 mg of4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(2-(pyrrolidin-1-yl)ethyl)benzamideas an off-white solid. LCMS [M+1]⁺561.1.

Example 36 Synthesis of Compound 235N-Benzyl-4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzamide

A mixture of4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoicacid (Compound 224, 68 mg, 0.14 mmol), benzylamine (22 mg, 0.21 mmol),HATU (70 mg, 0.18 mmol), and DIEA (40 μL, 0.21 mmol) in DMF (3 mL) wasstirred at room temperature for 3h. The crude reaction mixture waspurified by reverse phase HPLC (acetonitrile/water:TFA) to afford 51 mgofN-benzyl-4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzamideas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.22 (d, 1H), 9.12 (t,1H), 8.75 (d, 1H), 7.87 (t, 1H), 7.49 (dd, 1H), 7.40 (dd, 1H), 7.37-7.31(m, 4H), 7.29-7.24 (m, 1H), 4.51 (d, 1H), 2.69-2.63 (m, 2H), 2.55-2.44(m, 2H), 2.03-1.94 (m, 1H), 1.62-1.56 (m, 1H). LCMS [M+1]⁺554.5.

Example 37 Synthesis of Compound 2364-(7-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(2-(pyridin-2-yl)ethyl)benzamide

A mixture of4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoicacid (Compound 224, 70 mg, 0.15 mmol), 2-(pyridin-2-yl)ethanamine (24mg, 0.20 mmol), HATU (74 mg, 0.20 mmol), and DIEA (80 μL, 0.45 mmol) inDMF (3 mL) was stirred at room temperature overnight. The crude reactionmixture was purified by reverse phase HPLC (acetonitrile/water, 0.1%TFA). The fractions containing the desired compound were combined,acetonitrile was removed in vacuo, and the remaining aqueous layer wastreated with a saturated solution of sodium bicarbonate. The aqueouslayer was extracted with DCM (3×), the organics were combined, driedover sodium sulfate, and evaporated to dryness to afford 51 mg of4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(2-(pyridin-2-yl)ethyl)benzamideas a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.22 (d, 1H), 8.75 (d,1H), 8.66 (t, 1H), 8.52 (d, 1H), 7.82-7.70 (m, 2H), 7.47-7.22 (m, 4H),3.65 (q, 2H), 3.01 (t, 2H), 2.68-2.62 (m, 2H), 2.54-2.43 (m, 2H),2.03-1.93 (m, 1H), 1.60-1.57 (m, 1H). LCMS [M+1]⁺569.5.

Example 38 Synthesis of Compound 2374-(7-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(3-(pyrrolidin-1-yl)propyl)benzamide

A mixture of4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoicacid (Compound 224, 550 mg, 1.18 mmol),3-(pyrrolidin-1-yl)propan-1-amine (303 mg, 2.37 mmol), HATU (673 mg,1.77 mmol), and DIEA (0.6 mL, 3.54 mmol) in DMF (25 mL) was stirred atroom temperature overnight. Brine and EtOAc were added and the aqueouslayer was extracted with EtOAc (4×), the organics were combined, driedover sodium sulfate, and evaporated to dryness. The residue was purifiedby column chromatography on silica gel eluting with 0 to 20% MeOH/DCM toafford4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(3-(pyrrolidin-1-yl)propyl)benzamideas a pale orange solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.22 (d, 1H), 8.75(d, 1H), 8.64 (t, 1H), 7.83 (t, 1H), 7.47 (dd, 1H), 7.38 (dd, 1H), 3.35(m, 4H), 2.65-2.54 (m, 6H), 2.53-2.43 (m, 2H), 2.03-1.93 (m, 1H), 1.74(m, 6H), 1.64-1.53 (m, 1H). LCMS [M+1]⁺575.1.

The trifluoroacetic acid salt was prepared according to the followingprocedure: A mixture of4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoicacid (Compound 224, 70 mg, 0.15 mmol), 3-(pyrrolidin-1-yl)propan-1-amine(25 mg, 0.20 mmol), HATU (74 mg, 0.20 mmol), and DIEA (80 μL, 0.45 mmol)in DMF (3 mL) was stirred at room temperature overnight. The crudereaction mixture was purified by reverse phase HPLC (acetonitrile/water,0.1% TFA) to afford 60 mg of4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(3-(pyrrolidin-1-yl)propyl)benzamide2,2,2-trifluoroacetate as pale yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ9.47 (s, 1H), 9.22 (d, 1H), 8.75 (d, 1H), 8.68 (t, 1H), 7.86 (t, 1H),7.49 (dd, 1H), 7.41 (dd, 1H), 3.56 (m, 2H), 3.40-3.34 (m, 2H), 3.23-3.16(m, 2H), 3.07-3.96 (m, 2H), 2.70-2.64 (m, 2H), 2.54-2.43 (m, 2H),2.08-1.85 (m, 7H), 1.60-1.55 (m, 1H). LCMS [M+1]⁺575.6.

Compounds 238 to 311 were synthesized following the procedure describedin Example 35 from the appropriate acids and amines (amines were eithercommercially available or synthesized from literature procedures).

Example 39 Synthesis of Compound 3124-(7-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-6,8-dioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenzamide

A mixture of4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenzamide(synthesized as described for Example 1 using5-amino-3-(trifluoromethyl) picolinonitrile (Intermediate 1) and of4-((1-cyanocyclobutyl)amino)-2-fluoro-N-methylbenzamide (Intermediate21) as starting materials) (90 mg, 0.19 mmol) and H₂O₂ (30%, 0.72 mL) inMeOH (8 mL) was stirred at room temperature for 5 days. The reactionmixture was diluted with EtOAc (10 mL) and the organic layer was washedwith water, brine, and dried over magnesium sulfate. The residueobtained was purified by reverse phase HPLC (acetonitrile/water:TFA) toobtain 10 mg of4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-6,8-dioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenzamideas a white solid. 1H NMR (500 MHz, CDCl₃) δ 9.28 (d, 1H), 8.54 (d, 1H),8.23 (t, 1H), 7.33 (m, 1H), 7.27 (m, 1H), 6.93 (m, 1H), 3.07 (d, 3H),2.71 (m, 2H), 2.57 (m, 2H), 2.28 (m, 1H), 1.82 (m, 1H).

Example 40 Synthesis of Compound 3134-(7-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-N-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-2-fluorobenzamideStep 1:3-(4-(7-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzamido)propylmethanesulfonate

A mixture of4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(3-hydroxypropyl)benzamide(Compound 306, 80 mg, 0.15 mmol) and triethylamine (22 μL, 0.16 mmol) inTHF (5 mL) was cooled to 0° C. Methanesulfonyl chloride (23 μL, 0.3mmol) was added dropwise and the mixture was stirred at room temperatureovernight. Brine and EtOAc were added and the aqueous layer wasextracted with EtOAc (2×), the organics were combined, dried over sodiumsulfate, and evaporated to dryness to afford crude3-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzamido)propylmethanesulfonate that was used as is.

Step 2:4-(7-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-N-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-2-fluorobenzamide

A mixture of3-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzamido)propylmethanesulfonate (45 mg, 0.075 mmol), 3,3-difluoropyrrolidinehydrochloride (54 mg, 0.37 mmol), and triethylamine (0.14 mL, 1.05 mmol)in THF (2 mL) was heated to 70° C. overnight. Brine and EtOAc were addedto a cooled reaction mixture and the aqueous layer was extracted withEtOAc (2×), the organics were combined, dried over sodium sulfate, andevaporated to dryness. The residue obtained was purified by reversephase HPLC (acetonitrile/water:TFA) to obtain 4.2 mg of4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-N-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-2-fluorobenzamide.1H NMR (300 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.68 (d, 1H), 8.51 (t, 1H),7.72 (t, 1H), 7.39 (dd, 1H), 7.30 (dd, 1H), 3.25 (m, 4H), 2.80 (t, 2H),2.64-2.58 (m, 4H), 2.44-2.40 (m, 2H), 2.16 (m, 2H), 1.91 (m, 1H),1.64-1.45 (m, 3H). LCMS [M+1]⁺611.1.

Assays Example 41 AR In Cell Western Assay

LNCaP cells (8,000/well) were plated in RPMI media containing 10%Charcoal Dextran Stripped Serum into plates coated with poly-d-lysine.After 24 hours cells were treated with compound from 30 μM to 0.0003 μM.At 20 hours post compound addition the cells were fixed (30%formaldehyde in PBS) for 20′. Cells were permeabilized in PBS 0.1%Triton (50 μl/well, three times for 5′ each) and blocked with LiCorblocking buffer (50 μl/well, 90′). The wells were then incubatedovernight at 4° C. with the rabbit IgG androgen receptor antibody(AR-N20, Santa Cruz antibody) diluted 1:1000 in LiCor blockingbuffer/0.1% Tween-20. Wells were washed with 0.1% Tween-20/PBS (50μl/well, 5′ each) and then incubated in goat anti-rabbit IRDye™ 800 CW(1:1000) and DRAQ5 DNA dye (1:10,0000 for 5 mM stock) diluted in 0.2%Tween-20/0.01% SDS/LiCor blocking buffer in the dark (90′). Cells werewashed (50 μl/well, 5′ each) in 0.1% Tween-20/PBS. Wash buffer wasremoved and plates were read using the LiCor Odyssey.

Example 42 AR Fluorescent Polarization Assay (Invitrogen)

Compounds to be tested were diluted to 2× the final desiredconcentration in AR Green Assay Buffer (final DMSO: 0.6%). Fluormone ALGreen and the rat AR Ligand Binding Domain were diluted to 2× the finaldesired concentration (Fluormone: 2 nM, AR LBD: 50 nM) in AR Green AssayBuffer containing 2 mM DTT. The AR LBD/Fluormone solution was added toall the wells of a 384 well black plate (10 μl/well). The compounds wereadded to the AR LBD/Fluormone solution (10 μl/well). The plate wasincubated for 4 hours in the dark. The fluorescence polarization of eachwell was measured using an excitation wavelength of 485 nm and emissionwavelength of 530 nm.

Example 43 Prostate Cancer Cell Viability Assays

LNCaP, LNCaP AR, PC3, and VCaP cells were adjusted to a concentration of30,000 cells per mL in RPMI containing 10% FBS and 20 mM HEPES. 16microliters of the cell suspension was added to each well of a 384 wellplate, and the cells were incubated overnight to allow the cells toadhere. The following day a seven point, serial semilog dilution of eachcompound was added to the cells in 16 μL at a final concentrationranging from 30-0.003 μM. After 5 days' compound exposure, 16 μL ofCellTiter-GLo (Promega, Madison Wis.) was added to the cells the therelative luminescence units (RLUs) of each well was determinedCellTiter-Glo added to 32 μL of medium without cells was used to obtaina background value. The Percent viability of each sample was determinedas follows:

(RLU sample−RLU background/RLU untreated cells−RLU background)×100=%viability

Example 44 LNCaP-AR Luciferase Transcriptional Reporter Assays

LNCaP-AR-Luc were maintained in RPMI 1640 supplemented with 10% FCS(Cancer Res 2006; 66: (21). Nov. 1, 2006). Transcriptional assays wereperformed by seeding 100 μL of cells at a density of 25,000 cells/mLinto 96-well cell culture plates in RPMI 1640 supplemented with 10%charcoal stripped serum and allowed to attach overnight. For AR agonistassays, the compounds were serially diluted and 50 μL of compound plusRPMI 1640 supplemented with charcoal stripped serum was added to thecells. For AR antagonist assays, the compounds were serially diluted and50 μL of compound with RPMI plus R1881 supplemented with charcoalstripped serum were added to the cells. The final R1881 concentrationused in the antagonist assays was 0.1 nM. Following 40 hour incubationthe medium was removed and the cells were lysed in 40 μL of lysis buffer(25 mM Tris Phosphate, 2 mM CDTA, 10% Glycerol, 0.5% Triton X-100, 2 mMDTT). Firefly luciferase activity was measured immediately following theaddition of 50 μL luciferase buffer (20 mM tricine, 0.1 mM EDTA, 1.07 mM(MgCo₃)₄Mg(OH)_(2·)5H₂O, 2.67 mM MgSO₄, 33.3 mM DTT, 270 μM Coenzyme A,470 μM luciferin, 530 μM ATP).

Example 45 AR-VP16 DNA Binding Assays

HepG2 cells were maintained in RPMI 1640 supplemented with 10% FCS.AR-VP16 DNA binding assays were performed by seeding 100 μL of cells ata density of 250,000 cells/mL into 96-well cell culture plates in RPMI1640 supplemented with 10% charcoal stripped serum and allowed to attachovernight. Cells were transiently transfected using Lipofectin (LifeTechnologies) according to the manufacturer's protocol. Triplicatetransfections were performed using 33.3 ng AR-VP16 pCDNA3 (expressionvector), 66.7 ng 4×ARE-Luciferase (reporter vector), 16.7 ng CMVpRL(normalization vector), and 43.3 ng pCMX (filler DNA). Transfected cellswere incubated overnight then treated with ligand. For agonist assays,compounds were serially diluted and 50 μL of compound plus RPMI 1640supplemented with charcoal stripped serum was added to the cells. Forantagonist assays, the compounds were serially diluted and 50 μL ofcompound with RPMI supplemented with charcoal stripped serum plusmethyltrienolone (R1881) were added to the cells. The final R1881concentration used in the antagonist assays was 0.1 nM. Following 48hour incubation the medium was removed and the cells were lysed in 40 μLof lysis buffer (25 mM Tris Phosphate, 2 mM CDTA, 10% Glycerol, 0.5%Triton X-100, 2 mM DTT). Firefly luciferase activity was measuredimmediately following the addition of 40 μL luciferase buffer (20 mMtricine, 0.1 mM EDTA, 1.07 mM (MgCo₃)₄Mg(OH)_(2 ·)5H₂O, 2.67 mM MgSO₄,33.3 mM DTT, 270 μM Coenzyme A, 470 μM luciferin, 530 μM ATP). Renillaluciferase was measured following the addition of 40 μL colelenterazinebuffer (1.1 M NaCl, 2.2 mM Na₂EDTA, 0.22 M KχPO₄ (pH 5.1), 0.44 mg/mLBSA, 1.3 mM NaN₃, 1.43 μM coelenterazine, final pH adjusted to 5.0).

Illustrative biological data for representative compounds disclosedherein is presented in the following table:

ARVP16 ARVP16 DNA Binding Assay DNA Binding Assay (Antagonist mode):Compound # (Agonist mode): Agonist?¹ IC₅₀ <1.0 μM 1 No Yes 2 No No 3 NoNo 4 No Yes 5 No Yes 6 No Yes 7 No Yes 8 No No 9 No Yes 10 No No 11 NoYes 12 No Yes 13 No Yes 14 No No 15 No No 16 No Yes 17 Yes Yes 18 YesYes 19 No No 20 No Yes 21 No Yes 22 No Yes 23 No No 24 No No 25 No Yes26 Yes Yes 27 No Yes 28 No Yes 29 No Yes 30 No Yes 31 No Yes 32 No Yes33 No Yes 34 No No 35 No No 36 No Yes 37 No Yes 38 No No 39 Yes Yes 40No Yes 41 No Yes 42 No Yes 43 No Yes 44 No Yes 45 No Yes 46 No Yes 47 NoYes 48 No Yes 49 No Yes 50 No Yes 51 No Yes 52 No Yes 53 Yes Yes 54 NoNo 55 Yes Yes 56 No Yes 57 No Yes 58 Yes Yes 59 No Yes 60 Yes Yes 61 NoNo 62 No No 63 No Yes 64 No Yes 65 Yes Yes 66 Yes Yes 67 Yes Yes 68 NoNo 69 No Yes 70 No Yes 71 No No 72 Yes Yes 73 Yes Yes 74 Yes Yes 75 YesYes 76 Yes Yes 77 No No 78 No No 79 No Yes 80 No Yes 81 No No 82 No Yes83 No No 84 Yes Yes 85 Yes Yes 86 No Yes 87 No Yes 88 No Yes 89 No Yes90 No No 91 No No 92 No Yes 93 No No 94 No Yes 95 Yes Yes 96 No Yes 97Yes Yes 98 No Yes 99 Yes Yes 100 No Yes 101 No No 102 No No 103 No Yes104 No Yes 105 No Yes 106 No Yes 107 No Yes 108 Yes Yes 109 No Yes 110No Yes 111 No No 112 No Yes 113 No Yes 114 No No 115 No Yes 116 No Yes117 No No 118 No No 119 No Yes 120 No No 121 No No 122 No No 123 No No124 No Yes 125 No Yes 126 Yes Yes 127 No Yes 128 No Yes 129 No Yes 130No Yes 131 No Yes 132 No No 133 No Yes 134 No Yes 135 No Yes 136 No Yes137 No Yes 138 No No 139 No Yes 140 No No 141 Yes No 142 Yes Yes 143 YesYes 144 Yes Yes 145 Yes Yes 146 No Yes 147 No Yes 148 Yes Yes 149 No Yes150 Yes Yes 151 No No 152 No Yes 153 No Yes 154 No Yes 155 No No 156 YesYes 157 Yes Yes 158 No No 159 No No 160 No No 161 No No 162 No No 163 NoNo 164 No No 165 No No 166 No No 167 No No 168 No Yes 169 No Yes 170 YesYes 171 No Yes 172 No Yes 173 No Yes 174 No Yes 175 No Yes 176 No Yes177 No Yes 178 No Yes 179 Yes Yes 180 Yes Yes 181 Yes Yes 182 Yes Yes183 No Yes 184 Yes Yes 185 No Yes 186 Yes Yes 187 No Yes 188 No Yes 189No Yes 190 No Yes 191 No No 192 No No 193 No Yes 194 No Yes 195 No Yes196 No Yes 197 No No 198 No Yes 199 No Yes 200 Yes Yes 201 No Yes 202Yes Yes 203 No Yes 204 No Yes 205 No Yes 206 No Yes 207 No Yes 208 NoYes 209 No Yes 210 No No 211 No Yes 212 Yes Yes 213 Yes Yes 214 Yes Yes215 Yes Yes 216 No No 217 No Yes 218 No Yes 219 Yes Yes 220 No Yes 221No No 222 Yes Yes 223 No Yes 224 No No 225 No Yes 226 No No 227 No No228 No No 229 No Yes 230 No Yes 231 No Yes 232 No Yes 233 No No 234 NoNo 235 No Yes 236 No Yes 237 No Yes 238 No No 239 No No 240 No No 241 NoNo 242 No Yes 243 No No 244 No Yes 245 No No 246 No No 247 No No 248 NoNo 249 No Yes 250 No No 251 No No 252 No Yes 253 No No 254 No No 255 NoYes 256 No Yes 257 No Yes 258 No Yes 259 No Yes 260 No Yes 261 No Yes262 No Yes 263 Yes Yes 264 No Yes 265 No Yes 266 No Yes 267 No Yes 268No Yes 269 No Yes 270 No No 271 No No 272 No Yes 273 No Yes 274 No Yes275 No No 276 No No 277 No Yes 278 No Yes 279 No Yes 280 No Yes 281 NoYes 282 No Yes 283 No Yes 284 No Yes 285 No No 286 No Yes 287 No Yes 288No Yes 289 No Yes 290 No Yes 291 No Yes 292 No No 293 No Yes 294 No Yes295 No Yes 296 No Yes 297 No Yes 298 No Yes 299 No Yes 300 No Yes 301 NoYes 302 No Yes 303 No No 304 No Yes 305 No Yes 306 No Yes 307 No Yes 308No Yes 309 No Yes 310 No No 311 No No 312 No No 313 No Yes ¹Agonistdefined as a compound whose Emax in the ARVP16 DNA Binding Assay(Agonist mode) is >20x DMSO control

Example 46 GABA-Gated Cl Channel Antagonist Radioligand Binding Assay

Membrane homogenates of cerebral cortex (120 μg protein) are incubatedfor 120 min at 22° C. with 3 nM [³⁵S]-TBPS in the absence or presence ofthe test compound in a buffer containing 50 mM Na₂HPO₄/KH₂PO₄ (pH 7.4)and 500 mM NaCl. Nonspecific binding is determined in the presence of 20μM picrotoxinin Following incubation, the samples are filtered rapidlyunder vacuum through glass fiber filters (GF/B, Packard) presoaked with0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCl using a96-sample cell harvester (Unifilter, Packard). The filters are driedthen counted for radioactivity in a scintillation counter (Topcount,Packard) using a scintillation cocktail (Microscint 0, Packard). Theresults are expressed as a percent inhibition of the control radioligandspecific binding. The standard reference compound is picrotoxinin, whichis tested in each experiment at several concentrations to obtain acompetition curve from which its IC₅₀ is calculated.

In this assay, the following representative compounds disclosed hereindemonstrated an inhibition of less than 65% at 10 μM in the GABA-gatedCl— Channel Binding Assay: Compound 5, Compound 13, Compound 124,Compound 168, Compound 171, Compound 208, Compound 218, Compound 237,Compound 268, Compound 291.

In Vivo Assay(s)

Example 47 Castrate Resistant Prostate Cancer Xenograft Studies

Six to Seven week old male SCID Hairless Outbred mice (SHO, CharlesRivers Laboratories) underwent bilateral orchiectomy under isofluraneanesthesia. LNCaP/AR cells were grown in RPMI at 5% CO₂, 37° C. Cellswere spun down and re-suspended in 50% serum-free RPMI and 50% Matrigelat 1×10⁷ cells/ml. LNCaP/AR cells were subcutaneously injected (100μl/animal) on the right flank 3-5 days post castration. Tumor volume(length×width²/2) was monitored weekly. When tumors reached an averagevolume of ˜200 mm³ animals were randomized into treatment groups. Duringthe treatment period tumor volume was monitored bi-weekly. At thetermination of study tumors were collected and stored for furtheranalyses.

Pharmaceutical Compositions

Example 48 Parenteral Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection (subcutaneous, intravenous, and the like),100 mg of a water-soluble salt of a compound of Formula (I), (Ia), (II),(III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) isdissolved in sterile water and then mixed with 10 mL of 0.9% sterilesaline. The mixture is incorporated into a dosage unit form suitable foradministration by injection

In another embodiment, the following ingredients are mixed to form aninjectable formulation: 1.2 g of a compound of Formula (I), (Ia), (II),(III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X), 2.0mL of sodium acetate buffer solution (0.4 M), HCl (1 N) or NaOH (1 M)(q.s. to suitable pH), water (distilled, sterile) (q.s. to 20 mL). Allof the above ingredients, except water, are combined and stirred and ifnecessary, with slight heating if necessary. A sufficient quantity ofwater is then added.

Example 49 Oral Solution

To prepare a pharmaceutical composition for oral delivery, an aqueous20% propylene glycol solution is prepared. To this is added a sufficientamount of compound of Formula (I), (Ia), (II), (III), (IV), (V), (VI),(VII), (VIII), (VIIIa), (IX), (IXa) or (X) to provide a 20 mg/mLsolution of the compound of Formula (I), (Ia), (II), (III), (IV), (V),(VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X).

Example 50 Oral Capsule

To prepare a pharmaceutical composition for oral delivery, 100 mg of acompound of Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII),(VIII), (VIIIa), (IX), (IXa) or (X) is mixed with 750 mg of starch. Themixture is incorporated into an oral dosage unit such as a hard gelatincapsule, which is suitable for oral administration.

In another embodiment, 100 mg of a compound of Formula (I), (Ia), (II),(III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) isplaced into Size 4 capsule, or size 1 capsule (hypromellose or hardgelatin) and the capsule is closed.

Example 51 Oral Tablet

A tablet is prepared by mixing 48% by weigh of a compound of Formula(I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX),(IXa) or (X), 45% by weight of microcrystalline cellulose, 5% by weightof low-substituted hydroxypropyl cellulose, and 2% by weight ofmagnesium stearate. Tablets are prepared by direct compression. Thetotal weight of the compressed tablets is maintained at 250 mg.

Example 52 Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of acompound of Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII),(VIII), (VIIIa), (IX), (IXa) or (X) is mixed with 1.75 g ofhydroxypropyl celluose, 10 mL of propylene glycol, 10 mL of isopropylmyristate and 100 mL of purified alcohol USP. The resulting gel mixtureis then incorporated into containers, such as tubes, which are suitablefor topical administration.

The examples and embodiments described herein are for illustrativepurposes only and various modifications or changes suggested to personsskilled in the art are to be included within the spirit and purview ofthis application and scope of the appended claims.

What is claimed is:
 1. A compound of Formula (Ia), or a pharmaceutically acceptable salt thereof:

wherein, ring A is pyridinyl; m is 1, 2, 3 or 4; each R^(A) is independently halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰ , —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰, —CO₂R⁹, —N(R⁹)₂, —C(═O)N(R⁹)₂, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, or C₁-C₆alkoxy; both R¹ are taken together with the carbon atom to which they are attached to form a C₃-C₆cycloalkyl; X is S or O; ring B is phenyl; n is 1 or 2; each R⁴ is independently hydrogen, halogen, —CN, —NO₂, —OH, —OR⁹, —SR⁹, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —N(R¹¹)S(═O)₂R¹⁰, —S(═O)₂N(R⁹)₂, —C(═O)R¹⁰, —OC(═O)R¹⁰, —CO₂R⁹, —OCO₂R¹⁰, —N(R⁹)₂, —C(═O)N(R⁹)₂, —OC(═O)N(R⁹)₂, —NR¹¹C(═O)N(R⁹)₂, —NR¹¹C(═O)R¹⁰,—NR¹¹C(═O)OR¹⁰, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, or C₁-C₆alkoxy; R⁵ is -L¹-L²-R⁶ or L¹-R⁷; wherein (i) L¹ is —O—; and (ii) L² is C₁-C₆alkylene; R⁶ and R⁷ are independently an optionally substituted piperazinyl; said optional substituents being at least one of C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, —C(O)—(C₁₋₆ alkyl), —C(O)—O—(C₁₋₆ alkyl);—CH₂—C(O)—O—(C₁₋₆ alkyl), —(C₁₋₆ alkyl)sulfonyl, —(C₂₋₆ alkylene)-OH, or carbamoyl; each R⁹ is independently H, C₁-C₆alkyl, or C₁-C₆fluoroalkyl; R¹⁰ is independently C₁-C₆alkyl; and R¹¹ is independently H or C₁-C₄alkyl.
 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: X is S; both R¹ are taken together with the carbon atom to which they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and each R^(A) is independently halogen, —CN, —NO₂, —OH, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, or C₁-C₆alkoxy.
 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein each R⁴ is independently hydrogen, halogen, —CN, —NO₂, —OH, C₁-C₄alkyl, C₁₋₄fluoroalkyl, C₁-C₄fluoroalkoxy, or C₁-C₄alkoxy.
 4. The compound of claim 3, wherein m is 2 one R^(A) is —CN, or —NO₂, ; and the other R^(A) is halogen, —OH, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, or C₁-C₆alkoxy; n is 1; R⁴ is hydrogen, halogen, C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, or C₁-C₆alkoxy.
 5. The compound of claim 4, wherein the compound of Formula (Ia) has the structure of Formula (VI):

wherein, R⁴ is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄fluoroalkoxy, or C₁-C₄alkoxy; or is a pharmaceutically acceptable salt thereof.
 6. The compound of claim 5, wherein the compound of Formula (Ia) has the structure of Formula (IXa):

or is a pharmaceutically acceptable salt thereof.
 7. The compound of claim 6, wherein: R^(A) is —CH₃, —CF₃, or OCH_(3.)
 8. The compound of claim 6, wherein R⁵ is -L¹-L²-R⁶and L² is C₁-C₃alkylene.
 9. The compound of claim 6, wherein R⁵ is L¹-R⁷.
 10. The compound of claim 1, wherein: R^(A) is —CH₃, —CF₃, or OCH_(3;) both R¹ are taken together with the carbon atom to which they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; n is 0 or 1; and R⁴ is hydrogen or fluoro.
 11. The compound of claim 1, wherein R⁶ or R⁷ is piperazinyl optionally substituted with at least one C₁₋₆ alkyl, fluorinated C₁₋₆ alkyl, or —C(O)—(C₁₋₆ alkyl) .
 12. The compound of claim 1, wherein the compound is: 5-(5-(3-Fluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(3-Fluoro-4-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(4-Fluoro-3-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(4-Fluoro-3-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(3-Fluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-methyl-picolinonitrile; 5-(5-(3-Fluoro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(4-(2-(4-Methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(2-Fluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(2-Fluoro-4-(3 -(4-methylpiperazin-1-yl)propoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3 - (trifluoromethyl)- picolinonitrile; 3-Methyl-5-(8-oxo-6-thioxo-5-(4-(2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)ethoxy)phenyl)-5,7-diazaspiro[3.4]octan-7-yl)picolinonitrile; 3-Methyl-5-(5-(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-picolinonitrile; 5-(5-(4-(2-(4-Acetylpiperazin-1-yl)ethoxy)-3-fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile; or a pharmaceutically acceptable salt, or N-oxide thereof.
 13. A pharmaceutical composition comprising (a) a pharmaceutically acceptable carrier or excipient and (b) a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.
 14. The pharmaceutical composition of claim 13, wherein the compound is 5-(5-(3-Fluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(3-Fluoro-4-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(4-Fluoro-3-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(4-Fluoro-3-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(3-Fluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-methyl-picolinonitrile; 5-(5-(3-Fluoro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(4-(2-(4-Methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(2-Fluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(2-Fluoro-4-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 3-Methyl-5-(8-oxo-6-thioxo-5-(4-(2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)ethoxy)phenyl)-5,7-diazaspiro[3.4]octan-7-yl)picolinonitrile; 3-Methyl-5-(5-(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)- picolinonitrile; 5-(5-(4-(2-(4-Acetylpiperazin-1-yl)ethoxy)-3-fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile; or a pharmaceutically acceptable salt, or N-oxide thereof.
 15. A method of treating a patient with prostate cancer comprising administering to the patient a therapeutically effective amount of the compound of claim
 1. 16. The method of claim 15, wherein a compound of claim 1 is formulated in an oral dosage form.
 17. The method of claim 15, wherein the compound is: 5-(5-(3-Fluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(3-Fluoro-4-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(4-Fluoro-3-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(4-Fluoro-3-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(3-Fluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-methyl-picolinonitrile; 5-(5-(3-Fluoro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(4-(2-(4-Methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(2-Fluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(2-Fluoro-4-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 3-Methyl-5-(8-oxo-6-thioxo-5-(4-(2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)ethoxy)phenyl)-5,7-diazaspiro[3.4]octan-7-yl)picolinonitrile; 3-Methyl-5-(5-(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)- picolinonitrile; 5-(5-(4-(2-(4-Acetylpiperazin-1-yl)ethoxy)-3-fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile; or a pharmaceutically acceptable salt, or N-oxide thereof.
 18. The compound of claim 1, wherein the compound is: 5-(5-(3-Fluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(4-Fluoro-3-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(3-Fluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-methyl-picolinonitrile; 5-(5-(3-Fluoro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(4-(2-(4-Methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(2-Fluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 3-Methyl-5-(8-oxo-6-thioxo-5-(4-(2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)ethoxy)phenyl)-5,7-diazaspiro[3.4]octan-7-yl)picolinonitrile; 3-Methyl-5-(5-(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-picolinonitrile; 5-(5-(4-(2-(4-Acetylpiperazin-1-yl)ethoxy)-3-fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile; or a pharmaceutically acceptable salt, or N-oxide thereof.
 19. The compound of claim 1, wherein the compound is: 5-(5-(3-Fluoro-4-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(4-Fluoro-3 -(3 -(4-methylpiperazin-1-yl)propoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; 5-(5-(2-Fluoro-4-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile; or a pharmaceutically acceptable salt, or N-oxide thereof. 